Biphenomycin B and derivatives: Total synthesis and translation inhibition

Article abstract of DOI:10.1002/asia.201000908

A full account on the synthesis of the antibiotic natural product biphenomycin B and several derivatives is reported, which employs a Suzuki coupling reaction of a free carboxylic acid and macrolactam formation as key transformations. Liberal exchange of

Full text of DOI:10.1002/asia.201000908

FULL PAPERS
DOI: 10.1002/asia.201000908
Biphenomycin B and Derivatives: Total Synthesis and Translation Inhibition
Yu-Peng He,[a, b] Hao Tan,[a, b] Lars Arve,[a, b] Sascha Baumann,[a, b]
Herbert Waldmann,*[a, b] and Hans-Dieter Arndt*[a, b]
Abstract: A full account on the synthesis of the antibiotic natural product biphe-
nomycin B and several derivatives is reported, which employs a Suzuki coupling
Keywords: antibiotics
couplings · natural products · pep-
tides · synthesis design
·
cross
reaction of a free carboxylic acid and macrolactam formation as key transforma-
tions. Liberal exchange of the central amino acid was demonstrated. This proce-
dure gave derivatives to study the influence of the polar side chain of the central
amino acids on translation inhibition.
Introduction
clopeptide biphenomycin (1–3)[4] and arylomycin natural
products (4)[5] represent interesting case studies for chemical
syntheses and integrated biological studies. Both of them
display a biaryl amino acid embedded in a small peptide
macrocycle. Whilst the 15-membered ring biphenomycins 1
and 2 were reported to inhibit bacterial protein biosynthe-
sis,[6] the 14-membered ring arylomycins 4 bind to a bacterial
signal peptidase.[7]
In many biologically active natural products, key structural
elements often account for a particular biological activity
and hence may be regarded as “privileged”.[1] To identify
such privileged elements, the screening of compound libra-
ries has proven to be increasingly useful.[2] The biaryl subu-
nit is found in many biologically active molecules as an im-
portant privileged motif.[3] The structurally related biarylcy-
The biphenomycin biarylcyclopeptides[8] 1–3 are peptide
alkaloid antibiotics isolated from Streptomyces filipinensis[9]
and S. griseorubiginosus[10] by Ezaki et al.[11] The 15-mem-
bered ring compounds 1–3 carry two distinct structural fea-
tures: a biaryl moiety and a cyclic peptide with a hydroxyl
ated ornithine side chain.[12] Within the biphenomycin
family, biphenomycin A (1) has been most intensively stud-
ied. It shows antibacterial activity against Gram-positive
bacteria in vitro and in vivo. However, during in vitro test-
ing biphenomycin A was found to have quite a complex
spectrum of activity, which seemed to be dependent on ex-
perimental conditions as well. For example, biphenomycin A
was found to be highly active against Cornybacterium xero-
sis, but no activity could be observed with Staphylococcus
aureus and Streptococcus pyogenes in agar-diffusion tests at
200 mgmLꢀ1. This notwithstanding, biphenomycin A was sur-
prisingly effective in vivo in a mouse sepsis model.[9]
The nonhydroxylated congener biphenomycin B (1)
occurs together with biphenomycin A. Both molecules have
comparable activity in vitro.[13] Biphenomycin C (3) carries
an elongated peptide tag, which extends the C-terminus of
the peptide chain. This compound was shown to be a biosyn-
thetic precursor of biophenomycin A,[10b] thereby suggesting
a common predecessor peptide to be the starting material
for all the biphenomycins.
[a] Dr. Y.-P. He, H. Tan, Dr. L. Arve,+ Dr. S. Baumann,++
Prof. Dr. H. Waldmann, Dr. H.-D. Arndt+++
Max-Planck-Institute of Molecular Physiology
Department of Chemical Biology
Otto-Hahn-Straße 11,D-44227 Dortmund (Germany)
Fax : (+49)231-133-2498
E-mail: hans-dieter.arndt@mpi-dortmund.mpg.de
herbert.waldmann@mpi-dortmund.mpg.de
[b] Dr. Y.-P. He, H. Tan, Dr. L. Arve,+ Dr. S. Baumann,++
Prof. Dr. H. Waldmann, Dr. H.-D. Arndt+++
Technische Universitꢀt Dortmund
Faculty of Chemistry
Otto-Hahn-Straße 6,D-44221 Dortmund (Germany)
[+] Current address:
BayerCropScience GmbH
Alfred-Nobel-Straße 50, D-40789 Monheim (Germany)
[
++] Current address:
Stanford University School of Medicine
Department of Biochemistry
279 Campus Drive, West Beckman Center, B469
Stanford, CA 94305-5307 (USA)
[
+++] New address:
Friedrich-Schiller-Universitꢀt Jena
Lehrstuhl fꢁr Organische Chemie I
Humboldstrasse 10, D-07743 Jena (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000908.
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Chem. Asian J. 2011, 6, 1546 – 1556

was planned from benzyl bromide 10. In the for-
ward sense, building blocks 5, 7, and 8 could be in-
dividually varied later, if so desired.
To put this planning into synthetic practice, 2-hy-
droxy-5-iodobenzaldehyde 12[20] was alkylated to
provide methyl ether 13 (92% yield, Scheme 2) and
subsequently reduced with diisobutylaluminum hy-
dride (DIBAL-H) to give benzyl alcohol 14 in 98%
yield. Next, alcohol 14 was transformed into benzyl
bromide 10 by using phosphorus tribromide in
quantitative yield. We found bromide 10 to be
rather unstable on storage, hence 10 was immedi-
ately used for the next transformation. Amino acid
9 was prepared from benzyl bromide 10 by using Corey’s
asymmetric glycine enolate alkylation method, which utilizes
benzophenone imines for temporary protection.[21]
The molecular mode of action of the biphenomycin anti-
biotics currently remains unclear. In the patent literature it
was claimed that protein biosynthesis should be involved.[14]
However, full details were not given, and independent stud-
ies on this topic have not appeared. To prepare for investi-
gations of the mode of action of these compounds and to ex-
plore the bioactive biaryl scaffold, we developed a flexible
synthetic route to biphenomycin B.[15] For the synthesis, we
intended to concentrate on biphenomycin B (1) as a target
for the reasons of equal bioactivity, higher chemical stability,
and absence of the synthetically inconvenient benzylic hy-
droxy group.
Total syntheses of biphenomycins were reported previous-
ly by Schmidt[16] and later on by Zhu.[17] Studies on the syn-
theses of a considerable number of biphenomycin deriva-
tives which extend the Schmidt precedent were described in
patents from the Bayer research laboratories,[14,18] aiming at
acquiring SAR information and antibiotics development.[6]
In terms of synthetic strategy, the Schmidt synthesis em-
ployed enantioselective hydrogenations to furnish a biaryl
diamino diacid building block with homochiral termini, dif-
ferentiated by protecting groups. The Zhu laboratory has al-
ternatively shown that macrocyclization can be effectively
executed by an intramolecular Suzuki coupling of a peptide-
chain precursor. In our approach, we opted for biaryl forma-
tion by the Suzuki coupling, but with ring closure by macro-
lactam formation,[15] to enable liberal variation of the scaf-
fold. Here, we give a full account on our biphenomycin B
synthesis, detailed syntheses of a first set of derivatives, and
report biological tests for translation inhibition by these
compounds.
Scheme 1. Retrosynthetic disconnection of biphenomycin B (1) into
amino acid building blocks. Bpin=2,2,4,4-tetramethyl-1,3,2-dioxaboro-
lan-2-yl, Boc=tert-butoxycarbonyl, Cbz=benzyloxycarbonyl, TBS=tert-
butyldimethylsilyl.
Results
Retrosynthetically, we planned to disconnect biphenomy-
cin B (1) into amino acid 5 and the biaryl amino acid 6
(Scheme 1). Ornithine derivative 5 could be obtained from
trans-4-hyroxyproline.[19] The biaryl building block 6 could
be assembled from the o-tyrosine derivatives 7 and 8 by a
transition-metal-mediated coupling reaction. Both coupling
partners might be efficiently derived from the same amino
acid 9 by divergent protection and functionalization. To
obtain 9 in enantiopure form, a chiral amino acid synthesis
Scheme 2. Synthesis of amino acid 9 (as its hydrochloride). Reagents and
conditions: a) MeI (1.5 equiv), K2CO3 (1.5 equiv), acetone, reflux, 16 h,
92%; b) DIBAl-H (1.2 equiv), CH2Cl2, 08C, 2 h, 98%; c) PBr3
(0.34 equiv), toluene, 1008C, 50 min. quant.; d) Ph2C=GlyOtBu (11), O-
allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (10 mol%), CsOH
(10 equiv), CH2Cl2, ꢀ508C, 24 h; then 4m HCl in dioxane, RT, 16 h,
88%, >96% ee (HPLC).
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In our first experiments, the reactivity seemed to be quite
low at ꢀ788C, and the enantiomeric excess (ee) of product 9
varied from batch to batch. It was speculated that larger
amounts of product were only formed upon warming the re-
action mixture before workup. Therefore, a temperature
screen was conducted (ꢀ788C to 08C), which indicated an
optimal reaction temperature of ꢀ508C. By using these con-
ditions, both the yield and enantiomeric excess for amino
acid 9 were excellent, and the transformation could be relia-
bly conducted on a multi-gram scale.
To determine the enantiomeric excess of compound 9, it
was converted into its corresponding methyl ester 15
(Scheme 3) and independently derivatized with (R)-(+)- and
Scheme 4. Suzuki coupling with a free carboxylic acid 6. Reagents and
conditions: a) CbzCl (1.2 equiv), NaHCO3 (1.0 equiv), 1,4-dioxane/H2O
(1:1), 16 h, 74%; b) Boc2O (1.5 equiv), 2m NaOH (2 equiv), dioxane/H2O
(1:1), 16 h, 92%; c) MeI (1.5 equiv), K2CO3 (2 equiv), acetone, reflux,
16 h, 97%; d) (Bpin)2 (1.2 equiv), [PdCl
(3 equiv), DMSO, 808C, 16 h, 96%; e) 7 (1.0 equiv), 8 (1.2 equiv), Pd-
(OAc)2 (20 mol%), P(o-tolyl)3 (40 mol%), Cs2CO3 (3 equiv), 1,4-diox-
2ACHTUNGRTEN(NUNG dppf)] (5 mol%), KOAc
A
ACHTUNGTRENNUNG
ane/H2O (9:1), 808C, 16 h, 74%. dppf=bis(diphenylphosphino)ferro-
cene.
introduction of a Boc-group, methylester formation, and
Pd0-mediated borylation.[23] Biaryl acid 6 was produced in
74% yield by a Suzuki coupling reaction of iodide 7 with
boronate 8 using PdACHTNUTRGENNUG(OAc)2 as a catalyst, triACHTUNGTERN(NUGN o-tolyl)phos-
phine as a ligand, and Cs2CO3 as a base in dioxane/water
9:1 at 808C. This Suzuki coupling with a free carboxylic acid
saved not only a protecting group and two reaction steps,
but also afforded a simplified and flexible synthesis route.
The central hydroxyornithine amino acid was elaborated
from N-Boc-trans-4-hydroxyproline 19 (Scheme 5). Acid 19
was converted into its tert-butyl ester by using O-tert-butyl
isourea[24] and silylated to provide the tert-butyldimethylsilyl
(TBS) ether 20 in 64% yield. To enable functionalization,
pyrrolidine 20 was subjected to a regioselective a-oxidation
with a catalytic amount of RuO4,[25] which smoothly provid-
ed pyroglutamate 21 in 89% yield.[26] The activated amide
21 could be regioselectivity reduced with NaBH4 to give al-
Scheme 3. Synthesis of diastereomeric derivatives (S,S)-16 and (S,R)-16.
Reagents and conditions: a) SOCl2 (1.1 equiv), MeOH, reflux, 8 h, 93%;
b) (S)-(ꢀ)-1-phenylethyl isocyanate (3.0 equiv), pyridine (5.0 equiv),
CH2Cl2, RT, 16 h, 78%; c) (R)-(+)-1-phenylethyl isocyanate (3.0 equiv),
pyridine (5.0 equiv), CH2Cl2, RT, 16 h, 81%.
(S)-(ꢀ)-1-phenylethylisocyanate on analytical scale, to give
the two enantiomeric pairs (S,S)-16/ACHTGNUTREN(NGUN R,R)-16 and (S,R)-16/ACHTUGN-
TRENNUNG
(R,S)-16.[22] These diastereomers could be separated by
HPLC. An ee of 96–98% was
routinely determined from the
baseline separated isomers (see
the Supporting Information).
All peak assignments were con-
firmed by HPLC-MS.
Three orthogonal protecting
groups (Cbz, Boc, methyl ester)
were then installed on two
building blocks starting from
Scheme 5. Synthesis of protected hydroxyornithine 5. Reagents and conditions: a) O-tert-butyl N,N-diisopropy-
lisourea (2 equiv), THF, 608C, 16 h, 68%; b) TBSCl (1.2 equiv), DMAP (0.1 equiv), imidazole (2.6 equiv),
16 h, 94%; c) RuO2·nH2O (25 mol%), NaIO4 (3 equiv), EtOAc/H2O (1:2), 16 h, 89%; d) NaBH4 (5 equiv),
MeOH/NaPi buffer (1:1, pH 7.0), 08C!RT, 8 h, 62%; e) PPh3 (3 equiv), DIAD (3 equiv), HN3 (5 equiv), 4 h,
87%; f) TBSOTf (1.5 equiv), 2,6-lutidine (2 equiv), CH2Cl2, 15 min, then TBAF (1 equiv), THF/H2O (10:1),
the
same
compound
9
(Scheme 4). Cbz-protection of
amine hydrochloride 9 provided
iodide 7. Boronate 8 was ob-
tained in excellent yield after 70%.
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Total Synthesis
cohol 22 in 62% yield. The key for success was careful con-
trol of temperature and pH. Otherwise, deoxygenation and/
or over reduction led to formation of several side products.
Alcohol 22 was converted into the azide 23 by using a Mit-
sunobu displacement reaction with hydrazoic acid[27] in 87%
yield. In a last step, amine 5 was liberated by selective Boc-
group cleavage with TBSOTf[28] in 70% yield.
Biaryl acid 6 was then coupled with amine 5 using N-
ethyl-N-dimethylaminopropyl carbodiimide (EDC)·HCl, 1-
hydroxybenzotriazole (HOBt), and diisopropylethylamine
(DIPEA) in 78% yield (Scheme 6), and the resulting dipep-
salting by preparative HPLC. The NMR spectral data, as
well as the HRMS, IR, and optical rotation data were fully
consistent with those reported for natural biphenomycin B.
Additionally, we recorded a CD spectrum of the synthetic
material (see the Supporting Information). While no original
CD data for biphenomycin B (1) is available in the litera-
ture, the features found were similar to the ones reported
for biphenomycin A (2)[32] and a derivative of 1.[33] Notably,
the strong positive ellipticity around 220 nm indicated a neg-
ative dihedral angle of the biaryl linkage, that is, M- (or R-)
configuration. While there is no reason to believe in the ex-
istence of separable atropisomers for the biphenomycin scaf-
fold due to the absence of potentially locking o,o-disubstitu-
tion, the minimum conformation of the cyclopeptide array
still seems to program an M-configured axis for the biaryl
motif in solution.[34] Such a conformation had been inde-
pendently deduced earlier on for biphephenomycin A by a
combination of 2D NMR spectroscopy and molecular mod-
eling experiments.[32]
To study the influence of the side chain on the bioactivity
of biphenomycin B in some detail, the successful total syn-
thesis scheme was adapted to prepare three analogs with dif-
ferent side chains (Scheme 7). For this purpose, the biaryl
acid 6 was independently extended with tBu-protected l-ala-
nine-, serine-, and ornithine-tBu-ester using HOBt/EDC, to
give the biarylpeptides 26–28 in 82–85% yield. To prepare
for macrocycle formation, the tBu-based protecting groups
were removed by using 4N HCl in 1,4-dioxane. Macrocycli-
Scheme 6. Completion of the total synthesis of biphenomycin B (1). Re-
agents and conditions: a) EDC·HCl (1.5 equiv), HOBt (1.5 equiv), EtN-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
75%; d) PMe3 (9 equiv, 1m in toluene), THF/0.1m NaOH (9:1), RT, 8 h,
quant.; e) 1m HCl, RT, 16 h, quant.; f) BBr3 (1m in CH2Cl2, 20 equiv),
RT, 24 h, 52% (prep. HPLC). EDC=N-Ethyl-N-dimethylaminopropyl
carbodiimide, HOBt=1-hydroxybenzotriazole, HATU=7-aza-1-hydroxy-
benzotriazoluronium hexafluorophosphate, HOAt=7-aza-1-hydroxyben-
zotriazole, TESOTf=triethylsilyl trifluoromethanesulfonate.
tide 24 was then simultaneously Boc- and tBu-deprotected
with TESOTf[29] in quantitative yield, which retained the
TBS group. Other silyl triflates were either too reactive
(TMSOTf) or led to incomplete conversion (TBSOTf). Ring
closure was achieved by activation with HATU/HOAt[30] in
dry dichloromethane using a syringe pump to obtain macro-
cycle 25 in 75% yield. In our initial plan, we intended to
keep the azide intact as a potential diversification element
until the very last step. However, during deprotection ex-
periments we witnessed that strong Lewis acidic conditions
would induce unexpected decomposition reactions of the 2-
hydroxy azide side chain.
Therefore, the azide functional group was reduced first to
the amine by using PMe3 and aqueous hydroxide in quanti-
tative yield. These conditions unmasked the carboxy termi-
nus as well. Aqueous HCl was subsequently used for clean
removal of the TBS group, because it was found that the
secondary TBS ether was prone to SN2-type displacement
with bromide when treated with BBr3.[31] The 2-amino alco-
hol obtained could be treated with excess BBr3, which clean-
ly cleaved the Cbz and OMe groups. Biphenomycin B (1)
was finally obtained in 52% yield after purification and de-
Scheme 7. Synthesis of derivatves 32, 33, and 34 with different side
chains. Reagents and conditions: a) l-H-alanine-OtBu·HCl or l-H-serine-
OtBu·HCl or l-H-Orn(Z)-OtBu·HCl (1.2 equiv), EDC·HCl (1.2 equiv),
HOBt (1.2 equiv), EtN
ACHTUGNTERN(NUNG iPr)2 (2.2 equiv), CH2Cl2, RT, 16 h; b) 3m HCl,
1,4-dioxane/water, RT, 4 h, then 4m HCl, 1,4-dioxane/water, RT, 2 h;
c) slow addition to HATU (1.5 equiv), HOAt (1.5 equiv), EtNACHTUNGTRENNUNG(iPr)2
(2.2 equiv), CH2Cl2, RT, 30 h; d) I2 (32 equiv), Al (40 equiv), nBu4N+Iꢀ
(10 mol%), benzene, 108C, 1 h, then 608C, 15 min, then prep. HPLC.
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H.-D. Arndt and H. Waldmann et al.
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zation was executed as before and delivered the correspond-
ing biaryl cyclopeptides 29–31 in 39–72% yield. Interesting-
ly, the efficiency of ring closure seemed to be affected by
the type of side chain present at the central amino acid. In-
creasing its steric bulk was apparently supporting ring clo-
sure, as the yield of derivative 29 was significantly lower
than in the case of the bulky side chains 30, 31, and 25.
During studies which aimed at the final deprotection of the
molecule, we sometimes observed sluggish reactivity of
BBr3. After some screening of stronger Lewis acids, we
nents of the translational machinery in bacteria, but with
moderate affinity. In principle, such modest translation in-
hibition as observed here could correlate with the weak ef-
fects that biphenomycin has on the growth of many bacterial
strains in rich culture media in vitro. Nonetheless, such a
standard mode of action and the weak activity consequently
ensuing from it cannot easily account for the documented
activity of biphenomycin B in vivo. In fact, all antibiotics
tested here or elsewhere[37] with clearly assigned inhibition
activity at the ribosomeꢃs key components also gave strong
inhibition data in the test system used here. Therefore, it
might be hypothesized that biphenomycin could have addi-
tional activities, which are not picked up well in this target-
focused assay in vitro. To fully explain the context-depen-
dent activity of the biphenomycins, other regulatory or con-
ditional metabolic factors might contribute to the mode of
action. At least, our results cannot exclude that alternative
targets beyond the protein biosynthesis machinery could be
involved under certain experimental conditions or in vivo.
[35]
found that freshly prepared AlI3 efficiently provided the
fully deprotected biphenomycin derivatives. Despite the
higher activity of the reagent, no byproducts or epimeriza-
tion were observed when reaction times were kept short
(15 min). In this way, the target compounds 32–34 were ob-
tained in 64–69% yield after preparative HPLC purifica-
tion.
Biological Tests
Synthetic biphenomycin B (1) and the derivatives 32–34
were then tested for bacterial growth inhibition. In line with
previous reports,[6,8–13] we found it quite difficult to acquire
reliable growth inhibition data in liquid cell culture.[36]
Hence, we resorted to testing for bacterial translation inhibi-
tion, as the biphenomycins had been reported to inhibit pro-
tein biosynthesis.[14] We employed a coupled in vitro tran-
scription/translation assay, which measures protein biosyn-
thesis from the generation of fluorescence of a green fluo-
rescent protein (GFP)-encoding vector through E. coli ribo-
some translation.[37] In this target-based assay (Table 1), we
Conclusions
We have achieved a total synthesis of biphenomycin B from
three independent amino acid building blocks. The synthesis
is short (14 steps, 15% total yield) and flexible, as demon-
strated by the successful synthesis of three derivatives. Ini-
tial biological testing suggested that the biphenomycins in-
fluence translation, and clarified the influence of the side
chain, but a more complex interaction pattern or target is
likely. This observation is convergent with the efficacy of
the biphenomycins mostly developing in vivo, but much less
in vitro. Notably, the synthetic work developed herein will
provide tool compounds for clarifying this point in the
future.
Table 1. Translation inhibition by biphenomycin B and analogs in com-
parison with ribosomal inhibitors.
Compound
IC50 value
kirromycin
kanamycin
chloramphenicol
biphenomycin B (1)
32
33
34
0.38 mmꢁ0.01 mm
0.18 mmꢁ0.01 mm
3.0 mmꢁ0.5 mm
38 mmꢁ7.9 mm
>300 mm
Experimental Section
All reactions were carried out under an inert atmosphere of argon. 1H
and 13C nuclear magnetic resonance (NMR) spectra were recorded on a
Varian Mercury 400 or a Bruker DRX 400 (400.13 MHz and 100.61 MHz
respectively; 500.13 MHz and 125.61 MHz respectively), with chemical
shifts (d) reported in ppm relative to the solvent residual signals and cou-
pling constants reported in Hz. High resolution mass spectra (HRMS)
were measured on a Thermo Orbitrap coupled to a Thermo Accela
HPLC system, electrospray ionization (ESI), and fast atom bombardment
(FAB). Analytical HPLC-MS data were recorded on an Agilent HPLC
(1100 series) with a C18 column (CC125/4 NUCLEODUR C18 Gravity
5m) coupled to a Finnigan LCQ ESI spectrometer, detection: 280 nm;
flow rate: 1.0 mLminꢀ1; time: 15 min; solvents A: 0.1% HCOOH in
H2O, B: 0.1% HCOOH in MeCN, 1 min 10% B, in 10 min to 100% B.
Analytical GC MS data were recorded on a HP 6890 GC-MS system
based on electron impact detection (EI) using an high resolution gas
chromatography column (length: 25 m, I.D.: 0.2 mm, Film: 0.33 mm) and
a heating profile of ambient temperature to 1008C for 1 min, then for
5 min at 3008C, and then constant at 3008C for 5 min. Pre
parative HPLC was performed on an Agilent HPLC (1100 series) and
Waters HPLC 2767 by using a 125/21 NUCLEODUR C18 Gravity 5 m
column (Macherey & Nagel). For IR spectroscopy, a Bruker Tensor 27
FT equipped with an ATR and the OPUS software was used. Chromato-
approx. 200 mm
>300 mm
found synthetic biphenomycin B only moderately active
(38 mm) when compared to typical ribosomal inhibitors of
the large subunit (50S: chloramphenicol), the small subunit
(30S: kanamycin), or elongation factors (EF-TU: kirromy-
cin). Interestingly, the polar side chain seemed to have some
influence on the activity of the compound, although its influ-
ence could not be firmly assessed. When the amino group
was not present, activity was markedly reduced. Omission of
the hydroxy group or all of the functionality rendered the
compound completely inactive.
These data support the hypothesis that the biphenomycins
do inhibit protein biosynthesis in bacterial cells. The rather
modest activity suggests that 1 binds to one of the compo-
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Total Synthesis
graphic purification refers to flash chromatography using the indicated
solvents and Merck silica gel 60. Thin layer chromatography (TLC) was
performed using silica (Merck silica gel 60 F254 on aluminum foil). Com-
pounds on TLC were visualized by UV detection or staining with
KMnO4 solution. Melting points were determined using a Bꢁchi B-540
device and are uncorrected. Anhydrous solvents were purchased from
Fluka or Acros except for dichloromethane, which was distilled from cal-
cium hydride. All other solvents were used as supplied (analytical or
HPLC grade), without prior purification. Reagents were purchased from
Aldrich or Acros and used as supplied.
(S)-2-Amino-3-(5’-iodo-2’-methoxyphenyl)-propionic acid hydrochloride
(9)
A
mixture of diphenylmethyleneglycine tert-butyl ester (200 mg,
0.67 mmol, 1.0 equiv), cesium hydroxide monohydrate (1.2 g, 6.78 mmol,
10 equiv), and Coreyꢃs cinchonidine catalyst[21] (41.1 mg, 0.067 mmol,
0.1 equiv) in dichloromethane (50 mL) was cooled to ꢀ508C. A solution
of benzyl bromide 10 (443 mg, 1.35 mmol, 2.0 equiv) in toluene (30 mL)
was added dropwise over 1 h and the mixture was stirred at ꢀ508C for
16 h. After warming to room temperature, water (30 mL) was added and
the mixture was extracted with diethyl ether (3ꢄ30 mL). The combined
organic layers were washed with brine (30 mL), dried with MgSO4, con-
centrated, and purified by flash chromatography (silica gel, cyclohexane/
ethyl acetate/tri
5-Iodo-2-methoxybenzaldehyde (13)
A
mixture of 2-hydroxy-5-iodbenzaldehyde 12 (80.0 g, 0.32 mol,
1.0 equiv), iodomethane (92.9 g, 40.7 mL, 0.48 mol, 1.5 equiv), and potas-
sium carbonate (66.9 g, 0.48 mol, 1.5 equiv) in acetone (500 mL) was
heated to reflux for 16 h. After removal of the solvent, water (300 mL)
was added and the mixture was extracted with ethyl acetate (3ꢄ300 mL).
The combined organic layers were washed with brine (200 mL), dried
with MgSO4, and concentrated. The residue was dried in vacuo to furnish
13 (75.9 g, 0.29 mol, 92%) as a colorless solid. Rf =0.78 (cyclohexane/
ethyl acetate 2:1); m.p. 136–1388C. GC-MS (DB_50_S): tR =6.66 min, m/
z (relative intensity [%])=216 (9), 244 (18), 262 (100) [M]+. IR: n˜ =3231
(m), 2876 (m), 1665 (s), 1604 (s), 1463 (s), 1307 (s), 1271 (s), 1153 (s), 885
(s), 826 (s), 765 (s), 688 (m), 612 cmꢀ1 (s). 1H NMR (400 MHz, CDCl3):
d=3.91 (s, 3H), 6.78 (d, J=8.8 Hz, 1H), 7.80 (dd, J=8.8 Hz, 2.32 Hz,
1H), 8.08 (d, J=2.4 Hz, 1H), 9.82 ppm (s, 1H). 13C NMR (100 MHz,
CDCl3): d=56.5, 83.6, 114.8, 127.2, 137.8, 144.8, 162.1, 188.9 ppm. HR-
MS (FAB): calcd for C8H8IO2: 262.9569 [M+H]+; found: 262.9593.
ethylamine 95:5:1). The resulting product (Rf =0.32 in cyclohexane/ethyl
acetate 3:1) was dissolved in 1,4-dioxane (20 mL). A saturated aqueous
solution of HCl (10 mL) was added dropwise. After stirring at room tem-
perature for 16 h, ethyl acetate (30 mL) was added and the mixture was
extracted with water (3ꢄ25 mL). The aqueous extracts were concentrat-
ed and dried in vacuo to furnish the product 9 as a colorless solid. Yield:
314 mg, 0.59 mol, 88%; m.p.>2288C (decomp.); ee> 96%; ½aꢂ2D0 =+8.9
(MeOH, C=0.5). HPLC-ESI: tR =6.68 min; m/z=322.01 [MꢀClꢀ]+. IR:
n˜ =3596 (m), 3276 (m), 2889 (s), 2640 (w), 1735 (s), 1569 (m), 1521 (s),
1484 (s), 1251 (s), 1204 (s), 1120 (s), 1027 (s), 880 (m), 806 (s), 614 cmꢀ1
(m). 1H NMR (400 MHz, CD3OD): d=3.07 (dd, J=3.8, 7.12 Hz, 1H),
3.35 (dd, J=2.74, 6.5 Hz, 1H), 3.89 (s, 3H), 4.25 (dd, J=7.64, 7.60 Hz,
1H), 6.87 (d, J=8.60 Hz, 1H), 7.55 (d, J=2.32 Hz, 1H), 7.65 ppm (dd,
J=2.00 Hz, 1H). 13C NMR (100 MHz, CD3OD): d=32.9, 54.6, 56.7, 83.9,
115.1, 127.2, 140.1, 141.5, 159.9, 171.8 ppm. HR-MS (FAB): calcd for
C10H13INO3+: 321.9935 [MꢀClꢀ]+; found: 321.9927.
2-Methoxy-5-iodobenzyl alcohol (14)
Aldehyde 13 (4.0 g, 15.0 mmol, 1.0 equiv) was dissolved in abs. dichloro-
methane (40 mL) and cooled to 08C. A solution of diisobutylaluminum
hydride (1m in toluene, 18 mL, 18.0 mmol, 1.2 equiv) in toluene was
added dropwise over 1 h and the mixture was stirred for 2 h. Saturated
aqueous potassium sodium tartrate was added (30 mL) and the mixture
was stirred for 5 h. The reaction mixture was warmed to room tempera-
ture and extracted with dichloromethane (3ꢄ30 mL). The combined or-
ganic layers were washed with brine (40 mL), dried with MgSO4, and
concentrated. The residue was dried in vacuo to furnish alcohol 14 as a
colorless solid. Yield: 3.88 g, 14.7 mmol, 98%. Rf =0.34 (cyclohexane/
ethyl acetate 3:1); m.p. 92–938C. GC-MS (DB_50_S): tR =4.52 min; m/z
(relative intensity [%])=264 (100), [M]+. IR: n˜ =3286 (m), 2957 (m),
2835 (m), 1480 (s), 1439 (s), 1365 (s), 1239 (s), 1171 (s), 1126 (m), 1029
(s), 877 (s), 880 (m), 798 (s), 612 cmꢀ1 (s). 1H NMR (400 MHz, CDCl3):
d=2.06 (s, 1H), 3.83 (s, 3H), 4.62 (s, 2H), 6.65 (d, J=8.4 Hz, 1H), 7.55
(dd, J=8.4 Hz, 2.12 Hz, 1H), 7.59 ppm (d, J=2.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d=55.8, 61.5, 83.2, 112.9, 132.0, 137.4, 137.8,
157.5 ppm. HR-MS (FAB): calcd for C8H9IO2: 263.9647 [M]+; found:
263.9640.
(S)-2-(tert-Butyloxycarbonylamino)-3-(5’-iodo-2’-methoxyphenyl)-
propionic acid (17)
A mixture of amino acid hydrochloride 9 (2.00 g, 5.59 mmol, 1.0 equiv)
and aqueous sodium hydroxide (2m, 5.6 mL, 11.2 mmol, 2.0 equiv) in 1,4-
dioxane/water 1:1 (50 mL, v/v) was cooled to 08C. A solution of di-tert-
butyl dicarbonate (1.83 g, 8.39 mmol, 1.5 equiv) in dioxane (2 mL) was
added dropwise over 10 min. After the addition, the reaction mixture
was stirred for 16 h at room temperature. Subsequently, the pH of the re-
action mixture was adjusted to pH 2 with 1N hydrochloric acid. The mix-
ture was extracted with ethyl acetate (3ꢄ25 mL). The combined organic
layers were washed with brine (30 mL), dried with MgSO4, and concen-
trated. The crude product was purified by flash chromatography (silica
gel, dichloromethane/MeOH 7:1) to give Boc-protected amine 17 as a
colorless solid. Yield: 2.16 g, 5.13 mmol, 92%. Rf =0.46 (dichlorome-
thane/MeOH 7:1); m.p. 121–1248C. ½aꢂ2D0 =+13.3 (MeOH, c=1.0).
HPLC-ESI: tR =10.21 min. IR: n˜ =3277 (m), 2921 (m), 1734 (s), 1568
(m), 1521 (s), 1484 (s), 1250 (s), 1203 (s), 1120 (s), 1027 (s), 880 (m),
1
805 cmꢀ1 (s). H NMR (400 MHz, CD3OD): d=1.39 (s. 9H, 3ꢄCH3), 2.76
(dd, J=3.72, 6.41 Hz, 1H), 3.16–3.21 (dd, J=4.88 6.74 Hz, 1H), 3.86 (s,
3H), 4.42 (dd, J=4.88, 4.78 Hz, 1H), 6.77 (dd, J=8.60 Hz, 1H), 7.46 (d,
J=2.16 Hz, 1H), 7.53 ppm (dd, J=8.56, 2.12 Hz, 1H). 13C NMR
(100 MHz, CD3OD): d=29.6, 34.6, 56.8, 81.3, 83.5, 138.9, 138.9, 141.6,
160.1, 166.8 ppm. HR-MS (FAB): calcd for C15H20INO5: 421.0386 [M];
found: 421.0416.
2-Methoxy-5-iodobenzyl bromide (10)
Alcohol 14 (3.36 g, 12.8 mol, 1.0 equiv) was dissolved in toluene (50 mL)
and heated to 408C for 20 min. Phosphorus tribromide (0.41 mL,
4.36 mmol, 0.34 equiv) was added dropwise and the mixture was stirred
at 1008C for 50 min. After cooling to room temperature, the mixture was
washed with water (2ꢄ20 mL) and brine (20 mL). The organic layer was
dried with magnesium sulphate and filtered to obtain 2-methoxy-5-iodo-
benzyl bromide as a solution in toluene. The product 10 could only be
stored in a toluene solution, as it quickly decomposed after concentra-
tion. Yield: quantitative (GC-MS). Rf =0.76 (cyclohexane/ethyl acetate
3:1). GC-MS (DB_100_S): tR =4.96 min; m/z (relative intensity [%])=
217(27), 247 (100), 326 (12) [M]+. IR: n˜ =2938 (w), 2838 (w), 1624 (m),
1484 (s), 1433 (m), 1298 (m), 1249 (s), 1209 (s), 1149 (s), 1121 (s), 882
(S)-2-tert-Butyloxycarbonylamino-3-(2’-methoxy-5’-iodphenly)propionic
acid methyl ester (18)
Tyrosine derivative 17 (2.11 g, 5.0 mmol, 1.0 equiv), potassium carbonate
(1.38 g, 10.0 mmol, 2.0 equiv), and iodomethane (0.47 mL, 7.5 mmol,
1.5 equiv) were suspended in acetone (40 mL) and heated to reflux for
20 h. After cooling to room temperature, the solvent was removed, the
residue was treated with water (30 mL), and extracted with ethyl acetate
(3ꢄ30 mL). The combined organic layers were washed with brine
(30 mL), dried with MgSO4, and concentrated. The crude product was
purified by flash chromatography (silica gel, cyclohexane/ethyl acetate
3:1) to give methyl ester 18 as a yellow solid. Yield: 2.1 g, 4.8 mmol,
97%. Rf =0.49 (cyclohexane/ethyl acetate 3:1). HPLC-ESI: tR =
10.21 min; m.p. 174–1768C. ½aꢂ2D0 =+12.9 (MeOH, c=1.5). IR: n˜ =3367
1
(m), 862 (m), 802 (s), 737 (m), 611 cmꢀ1 (s). H NMR (400 MHz, CDCl3):
d=3.87 (s, 3H), 4.45 (s, 2H), 6.65 (d, J=8.8 Hz, 1H), 7.57 (dd, J=8.56,
2.12 Hz, 1H), 7.61 ppm (d, J=2.16 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d=27.7, 56.1, 82.7, 113.6, 129.0, 139.1, 139.6, 157.7 ppm.
Chem. Asian J. 2011, 6, 1546 – 1556
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1551

H.-D. Arndt and H. Waldmann et al.
FULL PAPERS
(w), 2975 (w), 1708 (s), 1489 (s), 1364 (m), 1251 (s), 1159 (s), 1048 (s),
1016 (s), 861 (w), 811 cmꢀ1 (m). 1H NMR (400 MHz, CD3OD): d=1.39
(s, 9H), 2.77 (dd, J=4.68, 6.64 Hz, 1H), 3.17–3.21 (dd, J=6.64, 2.74 Hz,
1H), 3.71 (s, 3H), 3.86 (s, 3H), 4.44 (dd, J=5.68, 5.44 Hz, 1H), 6.77 (dd,
J=8.60 Hz, 1H), 7.43 (s, 1H), 7.53 ppm (dd, J=8.6, 2.16 Hz, 1H).
13C NMR (100 MHz, CD3OD): d=29.5, 34.6, 53.4, 55.3, 56.9, 81.4, 83.8,
114.8, 130.2, 139.1, 141.6, 158.5, 160.0, 175.1 ppm. HR-MS (FAB): calcd
for C16H22INO5+: 435.0543 [M]+; found: 435.0513.
water (10 mL), and extracted with ethyl acetate (3ꢄ10 mL). The com-
bined organic layers were washed with brine (30 mL), dried with MgSO4,
and concentrated. The crude product was purified by flash chromatogra-
phy (silica gel, dichloromethane/MeOH 7:1) to give biaryl acid 3 as a col-
orless solid. Yield: 226 mg, 0.36 mmol, 74%. Rf =0.56 (dichloromethane/
MeOH 7:1); m.p. 113–1158C. ½aꢂ2D0 =+20.1 (MeOH, c=1.2). HPLC-ESI:
tR =9.79 min; m/z=659.15 [M+Na]+. IR: n˜ =3340 (w), 2939 (w), 1709
(s), 1069 (m), 1492 (s), 1437 (m), 1243 (s), 1162 (m), 1024 (s), 853 (m),
738 (m), 697 cmꢀ1 (m). 1H NMR (400 MHz, CD3OD): d=1.35 (s, 9H),
2.87–3.36 (m, 4H), 3.68 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 4.48 (m, 1H),
4.54 (m, 1H), 5.02 (m, 2H), 6.98 (m, 2H), 7.24 (m, 4H), 7.44 ppm (m,
5H). 13C NMR (100 MHz, CD3OD): d=25.9, 29.3, 56.8, 56.9, 68.3, 76.7,
112.6, 129.4, 129.6, 129.7, 130.3, 131.4, 138.9, 162.5, 168.9, 175.1 ppm. HR-
MS (FAB): calcd for C34H40N2O10Na+: 659.2575 [M+Na]+; found:
659.2550.
(S)-2-tert-Butyloxycarbonylamino-3-[2’methoxy-5’-(4’’,4’’,5’’,5’’-
tetramethyl 1’’,3’’,2’’-dioxaborolane-2’’-yl)phenyl]-propionic acid methyl
ester (88)
Iodide 18 (1.00 g, 2.3 mmol, 1.0 equiv) was dissolved in abs. DMSO
(20 mL). After addition of potassium acetate (0.68 g, 6.9 mmol,
3.0 equiv), the suspension was purged with argon for 30 min. Bis(pinaco-
lato)diboron (0.70 g, 2.76 mmol, 1.2 equiv) and [PdCl2ACTHUNTRGNE(UGN dppf)]·CH2Cl2
AHCTUNGTRENGN(UN 2S,4R)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-
(84.1 mg, 0.12 mmol, 0.05 equiv) was added and the reaction mixture was
heated to 808C for 4 h. After cooling to room temperature, water was
added (20 mL) and the mixture was extracted with ethyl acetate (3ꢄ
30 mL). The combined organic layers were washed with brine (30 mL),
dried with MgSO4, and concentrated. The crude product was purified by
flash chromatography (silica gel, cyclohexane/ethyl acetate 1:1) to give
boronate 8 as a yellow liqiud. Yield: 961 mg, 2.21 mmol, 96%. HPLC-
ESI: tR =10.49 min; m/z=336.00 [M+H-Boc]+. ½aꢂD20 =+1.8 (CHCl3, c=
1.0). IR: n˜ =2964 (w), 2874 (w), 1665 (s), 1585 (s), 1473 (s), 1389 (m),
1266 (s), 1243 (s), 1176 (s), 1121 (s), 1018 (s), 881 (s), 817 (s), 643 (s),
610 cmꢀ1 (s). 1H NMR (400 MHz, CD3OD): d=1.35 (s, 12H), 1.37 (s.
9H), 2.88 (dd, J=6.54, 8.76 Hz, 1H), 3.18 (dd, J=6.74, 6.64 Hz, 1H),
3.69 (s, 3H), 3.90 (s, 3H), 4.44 (dd, J=5.88, 5.76 Hz, 1H), 6.96 (d, J=
8.20 Hz, 1H), 7.51 (s, 1H), 7.66 ppm (dd, J=8.20 Hz, 1H). 13C NMR
carboxylic acid tert-butylester (20)
trans-N-Boc-4-hydroxyproline 19 (10.6 g, 46 mmol, 1.0 equiv) was dis-
solved in THF (20 mL), and O-tert-butyl isourea[24] (9.2 g, 46 mmol,
1.0 equiv) was added dropwise. The mixture was heated to 608C for 4 h.
A second equivalent of O-tert-butyl isourea (9.2 g, 46 mmol, 1.0 equiv)
was added at 608C and stirring was continued for 16 h. After cooling to
room temperature, the mixture was filtered and the solvent was removed
in vacuo. The residue was purified by flash chromatography (silica gel,
cyclohexane/ethyl acetate 9:1!5:1). The tert-butylester was dissolved in
dimethylformamide (85 mL), and 4-dimethylaminopyridine (DMAP;
0.54 g, 4.6 mmol, 0.1 equiv), imidazole (8.2 g, 120 mmol, 2.6 equiv), and
TBSCl (8.4 g, 55 mmol, 1.2 equiv) were added at 08C. The mixture was
stirred at room temperature for 16 h, diluted with water (250 mL), and
extracted with ethyl acetate (3ꢄ500 mL). The combined organic layers
were washed with brine (200 mL), dried with MgSO4, and concentrated.
After removal of the solvent, the crude product was purified by flash
chromatography (silica gel, cyclohexane/ethyl acetate 7:1) to give the
TBS-protected proline derivative 20 as a colorless liquid. Yield: 11.9 g,
29.4 mmol, 64%. Rf =0.40 (cyclohexane/ethyl acetate 5:1); m.p. 51.2–
52.18C. ½aꢂ2D0 =ꢀ51.6 (MeOH, c=1). IR: n˜ =2976 (m), 2930 (m), 1719 (s),
1684 (m), 1472 (w), 1410 (s), 1366 (s), 1309 (s), 1157 (s), 1088 (s), 833 (s),
807 (s), 774 cmꢀ1 (s). 1H NMR (400 MHz, CDCl3): d=0.04 (s, 6H), 0.85
(s, 9H), 1.42 (s. 9H), 1.44 (s. 9H), 1.94–2.00 (m, 1H), 2.07–2.19 (m, 1H),
2.23–3.36 (m, 1H), 3.52–3.60 (m, 1H), 4.16–4.27 (m, 1H), 4.38 ppm (t,
J=9.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): d=ꢀ4.9, 17.9, 25.7, 27.9,
28.3, 38.8, 39.7, 54.2, 54.6, 58.5, 58.7, 69.5, 70.3, 79.8, 80.9, 154.0,
172.2 ppm. HR-MS (FAB): calcd for C20H40NO5Si+: 402.2670 [M+H]+;
found: 402.2645.
(100 MHz, CD3OD): d=25.8, 29.3, 34.6, 53.2, 55.5, 56.5, 81.1, 111.5,
+
126.3, 137.4, 139.6, 162.5, 175.1 ppm. HR-MS: calcd for C22H34BNO7
:
435.2428 [M]+; found: 435.2413.
(S)-2-(Benzyloxycarbonylamino)-3-(5-iodo-2-methoxyphenyl)-propionic
acid (7)
Amino acid hydrochloride 9·HCl (2.0 g, 5.59 mmol, 1.0 equiv) and
sodium bicarbonate (0.59 g, 5.59 mmol, 1.0 equiv) were dissolved in
water/1,4-dioxane 1:1 (50 mL) and cooled to 08C. A solution of benzyl
chloroformate (0.94 mL, 6.70 mmol, 1.2 equiv) in dioxane (3 mL) was
added dropwise over 10 min. The reaction mixture was warmed to room
temperature and stirred for 16 h. Subsequently, the pH of the reaction
mixture was adjusted to pH 1 with 1N HCl and the mixture was extract-
ed with ethyl acetate (3ꢄ25 mL). The combined organic layers were
washed with brine (30 mL), dried with MgSO4, and concentrated. The
crude product was purified by flash chromatography (silica gel, dichloro-
methane/MeOH 7:1) to give acid 7 as a yellow liquid. Yield: 1.88 g,
4.14 mol, 74%. ½aꢂ2D0 =+8.3 (MeOH, c=0.73). HPLC-ESI: tR =9.21 min.
IR: n˜ =3304 (s), 3032 (m), 2940 (m), 1688 (s), 1587 (s), 1537 (s), 1430 (s),
1343 (m), 1246 (s), 1125 (s), 1055 (s), 1026 (s), 880 (m), 738 (m), 695 cmꢀ1
(s). 1H NMR (400 MHz, CDCl3): d=2.93–2.97 (dd, 3J=6.74, 6.84 Hz,
1H), 3.27 (dd, 3J=6.64, 6.94 Hz, 1H), 3.83 (s, 3H) 4.52 (dd, J=5.08 Hz,
1H), 5.03 (m, 2H), 6.67 (d, J=8.60 Hz, 1H), 7.33 (m, 5H), 7.48 (d, J=
2.16 Hz, 1-H), 7.55 ppm (dd, J=8.60, 2.16 Hz, 1H). 13C NMR (100 MHz,
(CD3)2OD): d=34.4, 56.8, 66.1, 68.3, 83.8, 114.8, 128.8, 129.1, 129.4,
129.7, 130.2, 130.3, 139.0, 141.6, 143.6, 159.2, 160.9, 181.0 ppm. HR-MS:
calcd for C18H18INO5: 455.0229 [M+H]+; found: 455.0260.
AHCTUNGERTG(NNUN 2S,4R)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsilyloxy)-5-
oxopyrrolidine-2-carboxylic acid tert-butylester (21)
RuO2·xH2O (40 mg, 0.3 mmol, 0.27 equiv) was added to a solution of
NaIO4 (836 mg, 3.9 mmol, 3.5 equiv) in distilled water (12 mL). The
yellow solution was stirred under an argon atmosphere at room tempera-
ture for 5 min and a solution of pyrrolidine 20 (451 mg, 1.12 mmol,
1.0 equiv) in ethyl acetate (9 mL) was added. Stirring was continued for
20 h at room temperature. The mixture was diluted with ethyl acetate
(30 mL) and filtered through a pad of celite. The organic layer was
washed with saturated aqueous NaHSO3 solution (10 mL), brine
(10 mL), and dried with MgSO4. After removal of the solvent, the crude
product was purified by flash chromatography (silica gel, cyclohexane/
ethyl acetate 9:1!7:1) to give pyrrolidine 21 as a colorless solid. Yield:
413 mg, 1.00 mmol, 89%; m.p. 65.0–65.58C. Rf =0.39 (cyclohexane/ethyl
acetate 5:1). ½aꢂ2D0 =+13.1 (MeOH, c=1). IR: n˜ =2929 (w), 2856 (w),
1797 (m), 1759 (s), 1723 (s), 1461 (m), 1392 (s), 1368 (s), 1308 (s), 1228
(s), 1138 (s), 970 (s), 882 (s), 777 cmꢀ1 (s). 1H NMR (400 MHz, CDCl3):
d=0.12 (s, 3H), 0.16 (s, 3H), 0.89 (s, 9H), 1.47 (s, 9H), 1.50 (s, 9H),
2.11–2.19 (m, 1H), 2.27–2.33 (m, 1H), 4.38–4.43 ppm (m, 2H). 13C NMR
(100 MHz, CDCl3): d=ꢀ5.35, ꢀ4.49, 18.2, 25.7, 27.9, 32.1, 55.8, 69.7,
82.4, 83.5, 149.4, 170.3, 172.1 ppm. HR-MS (FAB): calcd for
C20H38NO6Si+: 416.2463 [M+H]+; found: 416.2461.
ACHTUNGTRENNUNG(2S,2’’’S)-2-(Benzyloxcarbonylamino)-3-(4’,4’’-bis-methoxy-3’’-[tert-
butyloxy-carbonylamino-2’’’-methoxycarbonylethyl]-biphenyl-3’-yl)-
propionic acid (6)
Iodide
7 (218 mg, 0.48 mmol, 1.0 equiv) and boronate 8 (250 mg,
0.57 mmol, 1.2 equiv) were dissolved in 1,4-dioxane/water (10 mL, 9:1).
Cesium carbonate (469 mg, 1.44 mmol, 3.0 equiv) was added and the so-
lution was purged with argon for 30 min. Palladium(II) acetate (21.6 mg,
0.10 mmol, 0.2 equiv) and triACTHNUGRTENUNG(o-tolyl) phosphine (57.8 mg, 0.19 mmol,
0.4 equiv) were added and the reaction mixture was heated to 808C for
8 h. After cooling to room temperature, the mixture was diluted with
1552
www.chemasianj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 1546 – 1556

Total Synthesis
A
mixture was stirred for 15 min. After addition of a saturated NH4Cl solu-
tion, the reaction mixture was extracted with dichloromethane (2ꢄ
10 mL). After removal of the solvent, the residue was redissolved in
THF/H2O (10 mL/10:1). tetra-n-butylammonium fluoride (TBAF; 1m,
3.7 mL, 3.7 mmol, 1.0 equiv) was added to the solution and the mixture
was stirred for 1 h. Saturated NH4Cl solution was added (5 mL) and the
aqueous layer was extracted with diethylether (3ꢄ10 mL). The combined
organic extracts were washed with brine (10 mL), dried over MgSO4, and
concentrated. The crude product was purified by flash chromatography
(silica gel, cyclohexane/ethyl acetate 9:1!5:1) to give amine 23 as a col-
orless oil. Yield: 0.89 g, 2.6 mmol, 70%. Rf =0.40 (cyclohexane/ethyl ace-
tate 1:1). 1H NMR (400 MHz, CDCl3): d=0.08 (s, 6H), 0.90 (m, 9H),
1.39–1.45 (m, 12H), 1.62 (s, 2H), 1.78 (m, 1H), 3.46 (q, J=4.69 Hz, 1H),
3.62–3.77 (m, 3H). 13C NMR (100 MHz, CDCl3): d=ꢀ5.1, 18.5, 26.1,
28.3, 35.7, 42.3, 52.5, 60.1, 67.1, 81.6, 175.5. GC-MS: tR =5.30 min, m/z=
345. ½aꢂ2D0 =ꢀ73 (CHCl3, c=1.0). IR: n˜ =1158, 1254, 1741, 2121, 2859,
2931 cmꢀ1. HR-MS (FAB): calcd for C15H33N4O3Si+: 345.2316 [M+H]+;
found 345.2316.
A
solution of pyrrolidine 21 (3.5 g, 8.42 mmol, 1 equiv) in ethanol
(250 mL) was cooled to 08C. A buffer solution (NaHPO4/NaH2PO4,
80 mL, pH 7) and NaBH4 (1.6 g, 42.1 mmol, 5.0 equiv) were added and
the mixture was stirred at 08C for 2 h. More buffer was added (160 mL)
and stirring was continued at room temperature for 4 h. Subsequently,
the pH value was adjusted to pH 7 with NaH2PO4 and the mixture was
stirred for 16 h. Ethanol was removed in vacuo at room temperature, and
the aqueous layer was extracted with ethyl acetate (3ꢄ250 mL). The
combined organic layers were washed with brine (100 mL), dried with
MgSO4, and concentrated. The crude product was purified by flash chro-
matography (silica gel, cyclohexane/ethyl acetate 9:1!5:1) to give alco-
hol 22 as a colorless solid. Yield: 2.19 g, 5.22 mmol, 62%. Rf =0.33 (cyclo-
hexane/ethyl acetate 4:1); m.p. 65.5–68.28C. ½aꢂ2D0 =+13.1 (MeOH, c=1).
IR: n˜ =3433 (m), 2977 (w), 2930 (m), 2858 (m), 1714 (m), 1500 (m), 1391
(s), 1366 (s), 1252 (s), 1152 (s), 1060 (s), 835 (s), 776 (s), 668 cmꢀ1 (s).
1H NMR (500 MHz, CDCl3): d=0.07 (s, 6H), 0.90 (s, 9H), 1.43 (s, 9H),
1.46 (s, 9H), 1.45 (s, 9H), 1.80 (m, 1H), 1.95–1.98 (m, 1H), 3.47–3.50 (m,
1H), 3.59–3.62 (m, 1H), 3.78–3.79 (m, 1H), 4.21 (d, J=5.4 Hz, 1H),
5.39 ppm (d, J=5.45 Hz, 1H). 13C NMR (125 MHz, CDCl3): d=ꢀ5.2,
18.5, 26.1, 28.3, 28.6, 33.9, 52.1, 61.0, 66.9, 80.2, 82.4, 155.7, 171.8 ppm.
HR-MS (FAB): calcd for C20H42NO6Si+: 420.2776 [M+H]+; found:
420.2769.
(2S,5R,2’S,2’’’’S)-2’-(Benzyloxcarbonylamino)-3’-{4’’,4’’’-bis-methoxy-3’’’-
[2’’’’-tert-butyloxy-carbonylamino-2’’’-methoxycarbonylethyl]-biphenyl-3’’-
yl}-propanoylamino)-5-azido-4-(tert-butyldimethylsilyloxy) pentanoic acid
tert-butyl ester (24)
Biaryl acid 6 (162 mg, 0.25 mmol, 1.0 equiv), amine 5 (93.9 mg, 0.37 mol,
1.5 equiv), and HOBt (50.0 mg, 0.37 mmol, 1.5 equiv) were dissolved in
abs. dichloromethane (15 mL). N,N-Diisopropylethylamine (90.9 mL,
0.55 mmol, 2.2 equiv) was added, the mixture was cooled to 08C and
EDC·HCl (70.9 mg, 0.37 mmol, 1.5 equiv) was added. After stirring at
room temperature for 16 h, 0.5N aqueous H2SO4 (10 mL) was added and
the reaction mixture was extracted with dichloromethane (3ꢄ10 mL).
The combined organic layers were washed with brine (10 mL), dried with
MgSO4, and concentrated. The crude product was purified by flash chro-
matography (silica gel, cyclohexane/ethyl acetate 1:1) to give dipeptide
24 as a colorless solid. Yield: 191 mg, 0.2 mmol, 78%. Rf =0.63 (cyclohex-
ane/ethyl acetate 1:1); m.p. 134–1388C. ½aꢂ2D0 =+12.6 (MeOH, c=0.5).
HPLC-ESI: tR =12.89 min; m/z=985.25 [M+Na]+. IR: n˜ =3344 (m),
2978 (w), 2123 (s), 1732 (m), 1688 (m), 1652 (s), 1523 (s), 1495 (s), 1439
(s), 1245 (s), 1167 (s), 1167 (s), 1136 (s), 1025 (w), 805 (s), 742 cmꢀ1 (s).
1H NMR (400 MHz, CD3OD): d=0.12 (s, 6H), 0.94 (s, 9H), 1.35 (s, 9H),
1.35 (s, 9H), 1.45 (s, 9H), 1.70–1.89 (m, 2H), 2.89–3.00 (m, 2H), 3.19–
3.25 (m, 2H), 3.44–3.47 (m, 1H), 3.60 (dd, J=5.18, 5.28 Hz, 1H), 3.69 (s,
3H), 3.78 (dd, J=5.26 Hz, 1H), 3.92 (s, 6H), 4.46–4.53 (m, 1H), 5.01 (q,
J=10.68 Hz, 2H), 7.01 (d, J=8.36 Hz, 2H), 7.26 (m, 5H), 7.36–7.47 ppm
(m, 4H). 13C NMR (100 MHz, CD3OD): d=ꢀ4.8, 19.7, 26.9, 28.3, 28.8,
29.3, 33.9, 34.9, 52.6, 53.2, 56.7, 62.5, 68.3, 81.8, 83.7, 112.4, 112.5, 127.5,
129.4, 129.6, 130.1, 131.1, 138.7, 158.4, 158.9, 172.7, 175.1 ppm. HR-MS
(ESI): calcd for C49H70N6O12Si+: 963.4894 [M+H]+; found: 963.4894.
ACHTUNGTRENNUNG(2S,4R)-5-azido-2-(tert-butoxycarbonylamino)-4-(tert-
butyldimethylsilyloxy)pentanoic acid tert-butyl ester (23)
Preparation of a HN3 solution: NaN3 (6.5 g, 100 mmol), H2O (6.5 mL),
and toluene (40 mL) were combined in a flask under an argon atmos-
phere. The mixture was cooled to 08C and stirred vigorously, then con-
centrated H2SO4 (98%, 2.7 mL) was added dropwise. The mixture was
stirred at 08C for 15 min and dried by adding excess MgSO4. The concen-
tration of the supernatant HN3 solution in toluene was determined by ti-
tration of an aliquot against phenolphtaleine, with typical results between
1.2 and 1.6m. Caution: HN3 is a highly toxic, volatile, and an explosive
reagent, which should be freshly prepared and handled with extreme
care! To avoid potential hazards, the concentration of HN3 in toluene
should be kept lower than 2m, and excess HN3 should be immediately de-
stroyed by neutralizing with NaOH. Storing HN3 solutions for longer
than the duration of the experiment is strongly discouraged!
Mitsunobu Displacement
Alcohol 22 (2.11 g, 5.0 mmol, 1.0 equiv) and triphenylphosphine (3.93 g,
15.0 mmol, 3.0 equiv) were dissolved in toluene (80 mL). A solution of
HN3 in toluene (1.3m, 19.0 mL, 25.0 mmol, 4.0 equiv) and diisopropylazo-
dicarboxylate (DIAD; 3.19 g, 15.0 mmol, 3.0 equiv) was added dropwise
with protection under an argon atmosphere and stirred for 4 h. NaOH so-
lution was added (1m, 30 mL) and the aqueous layer was extracted with
ethyl acetate (3ꢄ50 mL). The combined organic layers were washed with
brine (30 mL), dried with MgSO4, and concentrated. The crude product
was purified by flash chromatography (silica gel, cyclohexane/ethyl ace-
tate 9:1!5:1 (v/v)) to give azide 23 as a colorless oil. Yield: 1.93 g,
4.35 mmol, 87%. Rf =0.50 (cyclohexane/ethyl acetate 4:1). ½aꢂ2D0 =ꢀ31.8
(MeOH, c=1). IR: n˜ =3347 (m), 2978 (w), 2931 (w), 2859 (w), 2120 (s),
1714 (s), 1501 (s), 1366 (s), 1251 (s), 1150 (s), 1119 (s), 836 (s), 776 (s),
667 cmꢀ1 (w). 1H NMR (400 MHz, CDCl3): d=0.07 (s, 6H), 0.90 (s, 9H),
1.44 (s, 9H), 1.45 (s, 9H), 1.64–1.72 (m, 1H), 1.75–1.82 (m, 1H), 3.45–
3.52 (m, 1H), 3.61–3.65 (m, 1H), 3.69–3.73 (m, 1H), 4.31 (m, 1H),
5.13 ppm (dd, J=6.88 Hz, 1H). 13C NMR (100 MHz, CDCl3): d=ꢀ5.6,
(4S,7S,10S,2’R)-10-Benzyoxycarbonylamino-11,21-bis-methoxy-7-[3’-azido-
2’-(tert-butyldimethyl-silyloxy)propyl]-5,8-diaza-6,9-dioxo-1,2
dibenzenacycloundecaphane-4-methyl carboxylate (25).
ACHTUNGTRNE(NUNG 4,2)-
Compound 24 (107.4 mg, 0.11 mmol, 1.0 equiv) and 2,6-lutidine
(202.0 mL, 471.6 mg, 4.4 mol, 40 equiv) were dissolved in abs. dichlorome-
thane (20 mL) and cooled to 08C. Triethylsilyl trifluoromethanesulfonate
(501 mL, 582 mg, 2.20 mol, 20 equiv) was added dropwise and the mixture
was stirred at room temperature for 16 h. Subsequently, a saturated
NH4Cl solution (15 mL) was added and the mixture was stirred vigorous-
ly for 4 h. The mixture was extracted with dichloromethane (3ꢄ5 mL).
The combined organic layers were washed with brine (5 mL), dried with
MgSO4, and concentrated. The residue was purified by flash chromatog-
raphy (silica gel, Rf =0.54 in dichloromethane/MeOH 10:1). The amino
acid obtained was dissolved in abs. dichloromethane (5 mL) and the solu-
tion was added dropwise at room temperature under vigorous stirring
over a period of 30 h by a syringe pump (flow rate 0.8 mL/h) to a solu-
tion of HATU (62.7 mg, 0.16 mmol, 1.5 equiv), HOAt (22.4 mg,
18.2, 25.7, 27.9, 28.3, 33.6, 51.8, 60.6, 66.5, 79.8, 82.1, 155.4, 171.4 ppm.
HR-MS (FAB): calcd for C20H41N4O5
445.2832.
:
445.2841 [M+H]+; found:
+
ACHTUNGTRENNUNG
0.16 mmol, 1.5 equiv), and EtNACTHNUTRGNE(UNG iPr)2 (37.8 mL, 29.6 mg, 0.24 mmol,
Azide 23 (1.66 g, 3.7 mmol, 1.0 equiv) and 2,6-lutidine (0.8 g, 7.5 mmol,
2.0 equiv) were dissolved in dichloromethane (10 mL). TBSOTf (1.47 g,
5.5 mmol, 1.4 equiv) was added dropwise at room temperature and the
2.2 equiv) in abs. dichloromethane (500 mL). After the addition was com-
plete, the reaction mixture was stirred for 8 h. The volatiles were re-
moved and the residue was dissolved in dichloromethane (40 mL),
Chem. Asian J. 2011, 6, 1546 – 1556
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1553

H.-D. Arndt and H. Waldmann et al.
FULL PAPERS
washed with aqueous 0.5N H2SO4 (10 mL), aqueous 1N NaHCO3
(10 mL), brine (10 mL), dried with MgSO4, and concentrated. The crude
product was purified by flash chromatography (silica gel, dichlorome-
thane/MeOH 13:1) to give cyclopeptide 25 as a colorless solid. Yield:
65.1 mg, 0.83 mmol, 75%. Rf =0.58 (dichloromethane/MeOH 13:1);
m.p. >2108C. (decomp.). ½aꢂD20 =+20.1 (DMSO, c=1.0). HPLC-ESI: tR =
10.69 min; m/z=767.1 [M+H]+. IR: n˜ =3266 (m), 2929 (m), 2857 (w),
2121 (s), 1643 (s), 1495 (s), 1244 (s), 1026 (w), 827 cmꢀ1 (s). 1H NMR
(400 MHz, [D6]DMSO): d=0.11 (s, 6H), 0.91 (s, 9H), 1.27 (m, 2H),
1.65–1.72 (m, 2H), 2.81–2.88 (m, 2H), 3.55–3.66 (m, 2H), 3.73 (s, 3H),
3.75 (s, 3H), 3.85 (s, 3H), 4.51 (t, J=5.96 Hz, 1H), 4.76–4.85 (m, 2H),
5.04–5.11 (q, J=10.08 Hz, 2H), 6.47 (d, J=7.24 Hz, 1H), 6.98–7.08 (m,
3H), 7.35–7.38 (m, 5H), 8.68 (d, J=9.04 Hz, 1H), 9.19 ppm (d, J=
9.04 Hz, 1H). 13C NMR (100 MHz, [D6]DMSO): d=ꢀ4.7, 18.7, 26.5, 34.3,
50.1, 51.8, 53.2, 55.0, 56.4, 61.1, 66.3, 67.1, 111.5, 122.4, 125.3, 127.0, 128.5,
128.6, 129.2, 130.5, 132.4, 132.6, 137.8, 156.5, 157.4, 170.8, 172.2,
172.7 ppm. HR-MS (ESI): calcd for C40H53N6O9Si+: 789.3638 [M+H]+;
found: 789.3640.
0.14 mmol, 84%. Rf =0.49 (cyclohexane/ethyl acetate 1:1); m.p. 122–
1258C. ½aꢂ2D0 =+6.4 (MeOH, c=0.5). HPLC-ESI: tR =11.21 min; m/z=
786.2 [M+Na]+. IR:n˜ =3307 (w), 2926 (w), 1709 (m), 1656 (m), 1493 (s),
1452 (m), 1243 (s), 1130 (m), 1026 (s), 808 (s), 772 (w), 738 (m), 697 (m),
637 cmꢀ1 (m). 1H NMR (400 MHz, CDCl3): d=1.24 (d, J=6.40 Hz), 1.34
(s. 9H), 1.40 (s. 9H), 3.06–3.17 (m, 4H), 3.68 (s, 3H), 3.82 (s, 6H), 4.35
(t, J=7.0 Hz, 1H), 4.51 (m, 1H), 4.53 (m, 1H), 5.01 (m, 2H), 5.26 (d, J=
7.60 Hz, 1H), 5.81 (m, 1H), 6.70 (m, 1H), 6.84 (t, J=7.4 Hz), 7.23–7.25
(m, 6H), 7.31–7.35 ppm (m, 3H). 13C NMR (100 MHz, CDCl3): d=18.8,
27.1, 28.2, 28.5, 33.3, 48.9, 52.3, 54.4, 55.7, 55.8, 56.5, 67.0, 79.8, 82.1,
110.7, 111.1, 125.3, 125.7, 126.7, 126.8, 128.1, 128.2, 128.7, 129.7, 129.9,
133.2, 133.6, 136.6, 155.5, 156.5, 156.7, 157.1, 170.9, 172.0, 173.1 ppm. HR-
MS (ESI): calcd for C41H54N3O11+: 764.3753 [M+H]+; found: 764.3753.
(2S,2’S,2’’’’S)-tert-Butyl-2’-(Benzyloxcarbonylamino)-3’-{4’’,4’’’-bis-
methoxy-3’’’-[2’’’’-tert-butoxycarbonylamino-2’’’-methoxycarbonylethyl]-
biphenyl-3’’-yl}-propanoylamino)-butyloxy-propanoate (27)
Dipeptide 27 was prepared from biaryl acid 6 (100 mg, 0.16 mmol) and l-
serine-tert-butylester hydrochloride (47.8 mg, 0.19 mol) according to gen-
eral procedure 1, and was obtained as a colorless solid after flash chro-
matography (silica gel, cyclohexane/ethyl acetate 1:1). Yield: 114 mg,
0.14 mmol, 85%. Rf =0.48 (cyclohexane/ethyl acetate 1:1); m.p. >125–
1278C (decomp.). ½aꢂ2D0 =+27.9 (MeOH, c=0.5). HPLC-ESI: tR =
11.86 min; m/z=858.32 [M+Na]+. 1H NMR (400 MHz, CDCl3): d=1.06
(s, 9H), 1.31 (s, 9H), 1.40 (s, 9H), 2.95–3.08 (m, 3H), 3.17–3.22 (m, 1H),
3.45 (d, J=6.4 Hz, 1H), 3.64 (s, 3H), 3.68–3.71 (m, 1H), 3.79 (s, 6H),
4.50–4.52 (m, 3H), 4.96 (s, 2H), 5.28 (d, J=7.6 Hz), 5.76 (m, 1H), 6.79–
6.84 (m, 3H), 7.20–7.22 (m, 5H), 7.31–7.33 ppm (m, 3H). 13C NMR
(100 MHz, CDCl3): d=27.4, 28.1, 28.4, 33.2, 33.9, 52.1, 53.4, 54.2, 55.6,
55.7, 56.1, 62.3, 66.7, 73.1, 77.4, 79.6, 81.9, 110.8, 110.9, 125.1, 125.8, 126.5,
Biphenomycin B (1)
Azide 25 (75 mg, 0.095 mmol, 1.0 equiv) was dissolved in THF/water
(10 mL, 9:1). A solution of trimethylphosphine in THF (380 mL, 1m in
THF, 0.38 mmol, 4.0 equiv) and 0.1N sodium hydroxide (2.8 mL,
0.28 mmol, 3 equiv) was added and the mixture was stirred for 6 h. The
volatiles were removed under reduced pressure and the residue was sus-
pended in 1m aqueous HCl. After stirring for 8 h, the mixture was con-
centrated and dried in vacuo. The residue was suspended in abs. dichloro-
methane (20 mL) and cooled to 08C. A solution of boron tribromide (1m
in dichoromethane, 1.9 mL, 1.9 mmol, 20 equiv) was added dropwise over
10 min and the reaction mixture was stirred at room temperature for 6 h.
Subsequently, the reaction mixture was cooled to 08C and abs. MeOH
(1 mL) and 0.1m aqueous lithium hydroxide (0.5 mL) were added. The
mixture was stirred for 5 min. After removal of the solvent, the crude
product was purified by preparative HPLC to give biphenomycin B as a
colorless solid. Yield: 23.4 mg, 0.05 mmol, 52%; m.p. >2158C.
(decomp.). ½aꢂ2D0 =+4.45 (1m HCl, c=0.375). HPLC-ESI: tR =2.25 min;
m/z=473.1 [M+H]+. IR: n˜ =3270 (m), 3078 (m), 2928 (w), 1637 (s), 1390
126.7, 127.9, 128.0, 128.5, 129.6, 133.2, 133.3, 136.5, 155.4, 156.2, 156.7,
+
156.9, 169.2, 171.3, 172.9 ppm. HR-MS (ESI): calcd for C45H62N3O12
:
836.4328 [M+H]+; found: 836.4328.
(2S,2’S,2’’’’S)-tert-Butyl-2’-(Benzyloxcarbonylamino)-3’-{4’’,4’’’-bis-
methoxy-3’’’-[2’’’’-tert-butyloxycarbonylamino-2’’’-methoxycarbonylethyl]-
biphenyl-3’’-yl}-propanoylamino)-2-benzyloxycarbonylamino-pentanoate
(28)
1
(s), 1242 (s), 848 cmꢀ1 (s). H NMR (500 MHz, [D6]DMSO): d=1.78–1.79
Dipeptide 28 was prepared from biaryl acid 6 (200 mg, 0.32 mmol) and l-
H-Orn(Z)-OtBu·HCl (135 mg, 0.38 mol) according to general procedure
1, and obtained as a colorless solid after flash chromatography (silica gel,
cyclohexane/ethyl acetate 1:1). Yield: 242 mg, 0.26 mmol, 82%; m.p. 141–
1438C. Rf =0.53 (cyclohexane/ethyl acetate 1:1). ½aꢂ2D0 =+13.6 (MeOH,
c=0.5). HPLC-ESI: tR =11.01 min; m/z=940.7 [M+H]+. IR: n˜ =3330
(w), 2936 (w), 1735 (m), 1692 (s), 1650 (s), 1520 (s), 1494 (m), 1390 (w),
1244 (s), 1160 (m), 1023 (s), 820 cmꢀ1 (w). 1H NMR (400 MHz, CDCl3):
d=1.29 (s, 11H), 1.35 (s, 9H), 1.55 (m, 1H), 1.70 (m, 1H), 2.98–3.07 (m,
6H), 3.64 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 4.33–4.36 (m, 2H), 4.47 (d,
J=6.0 Hz, 1H), 4.96 (s, 2H), 5.00 (m, 2H), 5.20 (d, J=7.2 Hz, 1H), 5.77
(d, J=4.4 Hz, 1H), 6.60 (d, J=6.8 Hz, 1H), 6.79–6.83 (m, 2H), 7.19–
7.32 ppm (m, 11H). 13C NMR (100 MHz, CDCl3): d=25.5, 28.3, 28.6,
30.1, 33.4, 40.8, 52.4, 52.6, 54.5, 54.5, 55.9, 55.9, 56.9, 66.9, 67.2, 79.9, 82.6,
111.1, 125.5, 126.8, 126.8, 128.2, 128.4, 128.4, 128.8, 128.8, 129.8, 130.2,
133.7, 136.7, 137.0, 155.6, 156.9, 157.3, 171.2, 171.3, 173.2 ppm. HR-MS
(ESI): calcd for C51H65N4O13+: 941.4543 [M+H]+; found: 941.4545.
(m, 1H), 1.95–1.98 (m, 1H), 2.73–2.78 (m, 1H), 2.94 (m, 1H), 3.03 (m,
1H), 3.31 (m, 1H), 3.57 (m, 3H), 3.88 (d, J=6.5 Hz, 1H), 4.13–4.35 (m,
1H), 4.79–4.80 (m, 1H), 6.80 (d, J=8.0 Hz, 2H), 6.95 (s, 1H), 7.21 (s,
3H), 8.72 ppm (s, 2H). 13C NMR (125 MHz, [D6]DMSO): d=29.5, 33.1,
35.3, 51.3, 51.6, 54.5, 55.0, 63.2, 116.2, 116.4, 124.4, 125.0, 125.1, 127.2,
128.0, 128.7, 131.7, 132.0, 154.8, 155.3, 170.6, 172.3, 176.7 ppm. 1H NMR
(400 MHz, D2O): d=2.17–2.22 (m, 2H), 2.92 (dd, J=5.60, 8.32 Hz, 1H),
3.05 (dd, J=7.62, 3.12 Hz, 1H), 3.42–3.46 (m, 1H), 3.58–3.60 (m, 1H),
3.74–3.79 (m, 1H), 3.90–3.93 (m, 1H), 4.54 (m, 1H), 4.75 (m, 1H), 4.85
(m, 1H), 6.91 (s, 1H), 6.95 6.98–6.99 (m, 2H), 7.16 (s, 1H), 7.44 (d, J=
8.40 Hz, 1H), 7.52 ppm (m, J=8.40 Hz, 1H). HR-MS (ESI): calcd for
C23H29N4O7+: 473.2031 [M+H]+; found: 473.2026.
General Procedure 1: Biaryl Peptide Extension
Carboxylic acid (1.0 equiv), amino acid-tert-butylester hydrochloride
(1.2 equiv), and HOBt (1.2 equiv) were dissolved in abs. dichloromethane
(20 mm, 1ꢄvol). After addition of N,N-diisopropylethylamine (2.2 equiv),
the mixture was cooled to 08C and EDC·HCl (1.2 equiv) was added.
After stirring at room temperature for 16 h, 1m aqueous HCl (1ꢄvol)
was added and the reaction mixture was extracted with CH2Cl2 (3ꢄvol).
The combined organic layers were washed with brine (1ꢄvol), dried with
MgSO4, and concentrated.
General Procedure 2: Deprotection and Macrolactam Formation
The protected precursor was dissolved in 1,4-dioxane/conc. HCl (3:1,
20 mm) and stirred for 3 h. More concentrated hydrochloric acid was
added (12.5 vol%!4m) and the mixture was stirred for 1 h. The solvent
was removed and the residue was dissolved in anhydrous dichlorome-
thane (5 mm=1 vol). This solution was added dropwise to a previously
(2S,2’S,2’’’’S)-tert-Butyl-2’-(benzyloxcarbonylamino)-3’-{4’’,4’’’-bis-
methoxy-3’’’-[2’’’’-tert-butyloxycarbonylamino-2’’’’-methoxycarbonylethyl]-
biphenyl-3’’-yl}-propanoylamino)-2-methylpropanoate (26)
prepared solution of HATU (1.5 equiv), HOAt (1.5 equiv), and EtNACHTUNGTRENNUNG(iPr)2
(2.2 equiv) in anhydrous dichloromethane (0.2 mm) with vigorous stirring
during 24 h by a syringe pump (flow rate 0.8 mL/h). After the addition
was complete, the mixture was stirred for 4 h and concentrated. The resi-
due was taken up in dichloromethane (1ꢄvol), washed with 1m HCl (1ꢄ
Dipeptide 26 was prepared from biaryl acid 6 (105 mg, 0.16 mmol) and l-
alanine-tert-butylester hydrochloride (35.9 mg, 0.19 mol) according to
general procedure 1, and obtained as a colorless solid after flash chroma-
tography (silica gel, cyclohexane/ethyl acetate 1:1). Yield: 105 mg,
1554
www.chemasianj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 1546 – 1556

Total Synthesis
vol), aqueous sodium bicarbonate (5 wt%, 1ꢄvol), brine (1ꢄvol), dried
with MgSO4, and concentrated.
General Procedure 3: Global Deprotection
The compound was dissolved in THF (50 mm, 1vol), and 0.1N aqueous
NaOH (8 equiv) was added. After stirring at room temperature for 8 h,
the solvent was removed. The residue was dried in vacuo, taken up in
benzene (4 mm, 1ꢄvol), added to a fresh solution of AlI3 (prepared from
aluminum gratings (40 equiv) and iodine (32 equiv) refluxed for 30 min
in anhydrous benzene (2 mLmmol of iodine)) and nBu4NI (0.1 equiv) at
108C, and stirred for 30 min at 108C. 2m HCl (50 vol%) was added at
108C, followed by EtOAc (3ꢄvol). The layers were separated and the or-
ganic layer was extracted with water (3ꢄ2 vol). The aqueous extracts
were combined and concentrated.
(4S,7S,10S)-10-Benzyloxycarbonylamino-11,21-bis-methoxy-7-methyl-5,8-
diaza-6,9-dioxo-1,2ACHTUNGTRENNUNG(4,2)-dibenzenaycloundecaphane-4-methyl carboxylate
(29)
Cyclopeptide 29 was prepared from peptide 26 (76.3 mg, 0.10 mmol) ac-
cording to general procedure 2, and obtained as a colorless solid after
flash chromatography (silica gel, dichloromethane/MeOH 10:1). Yield:
22.9 mg, 0.04 mmol, 39%. Rf =0.37 (dichloromethane/MeOH 19:1);
m.p. >2418C (decomp.). ½aꢂD20 =+21.7 (DMSO, c=0.33). HPLC-ESI: tR =
9.93 min; m/z=590.15 [M+H]+. IR: n˜ =3269 (s), 2925 (m), 2851 (w),
1745 (s), 1688 (s), 1634 (s), 1539 (s), 1494 (s), 1280 (m), 1246 (s), 1143
(m), 1028 (m), 800 (m), 697 cmꢀ1 (s). 1H NMR (400 MHz, [D6]DMSO):
d=1.28 (d, J=6.44 Hz, 3H), 2.83 (m, 2H), 3.35 (s, 3H), 3.42 (m, 2H),
3.75 (s, 3H), 3.84 (s, 3H), 4.51 (q, J=4.62 Hz, 1H), 4.72 (t, J=4.5 Hz,
1H), 4.85 (t, J=8.98 Hz, 1H), 5.08 (d, J=2.36 Hz, 2H), 6.23 (t, J=
7.6 Hz, 1H), 6.96–7.11 (m, 3H), 7.38 (m, 5H), 7.47–7.50 (m, 2H), 8.73 (d,
J=8.96 Hz, 1H), 8.95 ppm (d, J=8.80 Hz, 1H). 13C NMR (100 MHz,
[D6]DMSO): d=19.7, 27.5, 29.6, 53.3, 56.4, 66.3, 111.5, 128.5, 128.7, 129.2,
132.1, 132.4, 156.6, 157.4, 169.9 ppm. HR-MS (ESI): calcd for
C32H36N3O8+: 590.2497 [M+H]+; found: 590.2495.
(4S,7S,10S)-10-Amino-11,21-bis-hydroxy-7-methyl-5,8-diaza-6,9-dioxo-
1,2ACHTNUTRGNEUNG(4,2) dibenzenacycloundecaphan-4-carboxylic acid (32)
Cyclopeptide 29 (25.95 mg, 44 mmol) was deprotected according to gene
ral procedure 3 and the crude product was purified by preparative HPLC
to yield product 32 as a colorless solid. Yield: 12.3 mg, 0.03 mmol, 68%;
m.p. >2588C (decomp.). ½aꢂD20 =ꢀ24 (DMSO, c=0.2). HPLC-ESI: tR =
5.38 min; m/z=414.16 [M+H]+. IR: n˜ =3258 (m), 3079 (m), 2926 (m),
1678 (m), 1636 (s), 1438 (s), 1201 (s), 1134 (s), 873 (s), 722 cmꢀ1 (m).
1H NMR (400 MHz, [D6]DMSO): d=1.31 (d, J=7.04 Hz, 3H), 2.70–2.77
(m, 2H), 3.01–3.06 (m, 2H), 4.10 (m, 1H), 4.72–4.81 (m, 2H), 6.82–6.86
(m, 2H), 7.23 (m, 2H), 7.32 (m, 2H), 7.96 (m, 2H), 8.97 (d, J=8.6 Hz,
1H), 9.07 (d, J=9.36 Hz, 1H), 9.53 ppm (s, 2H). 13C NMR (100 MHz,
(4S,7S,10S)-10-Benzyloxycarbonylamino-11,21-bis-methoxy-7-
hydroxymethyl-5,8-diaza-6,9-dioxo-1,2ACTHNUGTRNEUNG(4,2)-dibenzenaycloundecaphan-4-
methyl carboxylate (30)
[D6]DMSO): d=24.7, 31.4, 35.1, 67.2, 68.2, 117.5, 129.0, 130.7, 159.1,
+
165.8, 170.2 ppm. HR-MS (ESI): calcd for C22H24N3O6
: 414.1660
Cyclopeptide 30 was prepared from peptide 27 (80.1 mg, 0.10 mmol) ac-
cording to general procedure 2 and obtained as a colorless solid after
flash chromatography (silica gel, dichloromethane/MeOH 10:1). Yield:
45.7 mg, 0.076 mmol, 59%. Rf =0.43 (dichloromethane/MeOH 10:1).
m.p. >2218C (decomp.). ½aꢂD20 =+28.4 (DMSO, c=0.5). HPLC-ESI: tR =
9.35 min; m/z=606.13 [M+H]+. IR: n˜ =3418 (m), 2914 (m), 2360 (s),
1731 (s), 1639 (s), 1496 (m), 1241 (s), 1171 (m), 1020 (s), 801 (m), 696
(m), 668 cmꢀ1 (m). 1H NMR (400 MHz, [D6]DMSO): d=2.89 (m, 2H),
3.29–3.41 (m, 2H), 3.55 (q, J=5.27 Hz, 1H), 3.62 (q, J=5.40 Hz, 1H),
3.73 (s, 6H), 3.84 (s, 3H), 4.56 (t, J=4.81, 2.76 Hz, 1H), 4.70 (t, J=
7.35 Hz, 1H), 4.82 (t, J=6.19 Hz, 1H), 4.91 (t, J=3.64 Hz, 1H), 5.10 (d,
J=2.38 Hz, 2H), 6.35 (d, J=7.44 Hz, 1H), 6.97–7.13 (m, 3H), 7.34–7.48
(m, 8H), 8.45 (d, J=8.96 Hz, 1H), 8.98 ppm (d, J=8.60 Hz, 1H).
13C NMR (100 MHz, [D6]DMSO): d=29.1, 31.3, 51.8, 53.2, 54.9, 55.5,
56.5, 62.9, 66.3, 111.6, 125.4, 125.8, 126.8, 126.9, 128.5, 128.7, 129.3, 132.2,
132.5, 137.9, 155.8, 156.6, 157.4, 170.7, 171.9 ppm. HR-MS (ESI): calcd
for C32H36N3O9+: 606.2446 [M+H]+; found: 606.2444.
[M+H]+; found: 414.1655.
(4S,7S,10S)-10-Amino-11,21-bis-hydroxy-7-hydroxymethyl-5,8-diaza-6,9-
dioxo-1,2(4,2)-dibenzenacycloundecaphan-4-carboxylic acid (33)
AHCTUNGTRENNUNG
Cyclopeptide 30 (10.2 mg, 16.87 mmol) was deprotected according to
general procedure 3 and the crude product was purified by preparative
HPLC to yield product 33 as a colorless solid. Yield: 4.67 mg, 10.8 mmol,
64%; m.p. >2488C (decomp.). ½aꢂ2D0 =ꢀ19.8 (DMSO, c=0.33). HPLC-
ESI: tR =5.05 min; m/z=429.9 [M+H]+. IR: n˜ =3270 (m), 2932 (m), 1670
(s), 1639 (s), 1441 (s), 1198 (s), 1134 (s), 981 (m), 826 (s), 798 (m),
721 cmꢀ1 (m). 1H NMR (400 MHz, [D6]DMSO): d=2.74 (dd, J=9.5 Hz,
1H), 3.05–3.09 (m, 1H), 3.24–3.30 (m, 2H), 3.54–3.65 (m, 2H), 4.15 (s,
1H), 4.69–4.79 (m, 2H), 5.03 (s, 1H), 6.81–6.87 (m, 2H), 7.00 (s, 1H),
7.19–7.30 (m, 3H), 8.01 (s, 2H), 8.96–9.02 (m, 2H), 9.55 (s. 1H),
9.76 ppm (s. 1H). 13C NMR (100 MHz, [D6]DMSO): d=29.1, 29.9, 51.7,
53.7, 55.3, 55.5, 62.9, 115.4, 115.9, 121.3, 124.7, 125.6, 126.3, 129.7, 130.5,
130.5, 131.8, 154.3, 155.1, 168.1, 170.3, 173.9 ppm. HR-MS (ESI): calcd
for C21H34N3O7+: 430.1609 [M+H]+; found: 430.1608.
(4S,7S,10S)-10-Benzyolxycarbonylamino-11,21-bis-methoxy-7-(3’-
(benzyloxy-carbonylamino)-propyl)-5,8-diaza-6,9-dioxo-1,2
ACHTUNGTRNE(NUNG 4,2)-
dibenzenaycloundecaphan-4-methyl carboxylate (31)
(4S,7S,10S)-10-Amino-11,21-bis-hydroxy-7-(3’-aminopropyl)-5,8-diaza-6,9-
dioxo-1,2ACTHNUTRGNE(UNG 4,2)-dibenzenacycloundecaphan-4-carboxylic acid (34)
Carboxylate 31 was prepared from peptide 28 (103 mg, 0.13 mmol)
according to general procedure 2 and obtained as a colorless solid after
flash chromatography (silica gel, dichloromethane/MeOH 10:1 v/v).
Yield: 72.3 mg, 0.09 mmol, 72%. Rf =0.48 (dichloromethane/MeOH 9:1).
m.p. >2208C (decomp.). ½aꢂD20 =+20.1 (DMSO, c=1). HPLC-ESI: tR =
10.69 min; m/z=767.1 [M+H]+. IR: n˜ =3273 (m), 2928 (w), 1740 (w),
1689 (s), 1638 (s), 1537 (s), 1494 (s), 1242 (s), 1131 (m), 1026 (m), 802
(m), 695 cmꢀ1 (s). 1H NMR (400 MHz, [D6]DMSO): d=1.44 (m, 2H),
1.62 (m, 1H), 1.94–2.01 (m, 1H), 2.75–2.81 (m, 2H), 2.97–2.99 (m, 2H),
3.35–3.40 (m, 1H), 3.66 (s, 6H), 3.78 (s, 3H), 4.48 (t, J=5.6 Hz, 1H), 4.57
(t, J=7.7 Hz, 1H), 4.78 (t, J=9.4 Hz, 1H), 4.98 (s, 2H), 5.02 (s, 2H) 6.18
(d, J=7.6 Hz, 1H), 6.90–6.96 (m, 2H), 7.04 (s, 1H), 7.23–7.42 (m, 13H),
8.61 (d, J=9.2 Hz, 1H), 8.93 ppm (d, J=8.8 Hz, 1H). 13C NMR
(100 MHz, [D6]DMSO): d=26.8, 28.9, 29.6, 31.3, 36.0, 51.5, 52.4, 53.2,
54.9, 56.4, 56.5, 66.1, 66.3, 111.6, 111.9, 125.2, 125.2, 125.3, 125.3, 125.7,
126.5, 126.5, 126.9, 128.6, 129.2, 129.6, 130.6, 132.1, 132.4, 137.9, 138.2,
155.8, 156.6, 157.0, 157.5, 170.3, 172.7, 172.8 ppm. HR-MS (ESI): calcd
for C42H47N4O10+: 767.3287 [M+H]+; found: 767.3287.
Cyclopeptide 31 (26 mg, 34.0 mmol) was deprotected according to general
procedure 3 and the crude product was purified by preparative HPLC to
yield product 34 as a colorless solid. Yield: 10.7 mg, 23.4 mmol, 69%;
m.p. >2378C (decomp.). ½aꢂD20 =ꢀ16.1 (DMSO, c=0.2). HPLC-ESI: tR =
4.30 min; m/z=457.1 [M+H]+. IR: n˜ =3021 (m), 2927 (m), 1721 (s), 1661
(m), 1550 (m), 1440 (s), 1262 (s), 987 (s), 823 (s), 763 cmꢀ1 (m). H NMR
1
(400 MHz, [D6]DMSO): d=1.70 (m, 4H), 2.76–2.79 (m, 4H), 2.99–3.02
(m, 2H), 4.14 (s, 1H), 4.67–4.68 (m, 2H), 6.81–6.92 (m, 3H), 7.17–7.25
(m, 3H), 8.14 (s, 6H), 9.02 ppm (m, 2H). 13C NMR (100 MHz,
[D6]DMSO): d=29.1, 29.8, 38.3, 40.1, 120.0, 125.2, 128.9, 130.2, 131.6,
154.8, 168.6, 171.0 ppm. HR-MS (ESI): calcd for C23H29N4O6+: 457.2081
[M+H]+; found: 457.2079.
Translation Inhibition Testing
The in vitro transcription/translation inhibition assay was performed in
384 well plates (Optiplate-384 F, PerkinElmer) using the RTS 100 E. coli
HY Kit (Roche Diagnostics) as described.[37] In brief, the plasmid DNA
template containing the GFP gene under the control of a T7 promoter
was used as provided. 6 mL of buffer I (20 mm Tris-HCl, 10 mm MgSO4,
20 mm NaCl, 5% trifluoroethanol (TFE; pH 7.4) were introduced per
Chem. Asian J. 2011, 6, 1546 – 1556
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1555

H.-D. Arndt and H. Waldmann et al.
FULL PAPERS
well, and serial dilutions (6 mL) of the compounds were prepared in trip-
licates. The final concentration of TFE was 5% in each well.
Ehlert, S. Raddatz, Y. Cancho Grande, M. Michels, S. Weigand, I.
Adelt, T. Lampe, 2005, WO 2005058943, 173 pp.; d) R. Endermann,
K. Ehlert, S. Raddatz, Y. Cancho-Grande, M. Michels, C. Freiberg,
J. Schuhmacher, S. Weigand, 2005, WO 2005118613, 97 pp; e) T.
Lampe, I. Adelt, D. Beyer, N. Brunner, R. Endermann, K. Ehlert,
H.-P. Kroll, F. von Nussbaum, S. Raddatz, J. Rudolph, G. Schiffer,
A. Schumacher, Y. Cancho-Grande, M. Michels, S. Weigand, 2005,
WO 2005033129, 181 pp; f) R. Endermann, K. Ehlert, C. Freiberg,
S. Raddatz, M. Michels, Y. Cancho-Grande, J. Schuhmacher, S. Wei-
gand, 2006, DE 102005014240, 197 pp.
2 mL of the reaction cocktail (containing no DNA template) were added
to each well. To start transcription, 2 mL of the diluted plasmid (20:1)
were added to each well to reach a total volume of 10 mL. The plates
were sealed and incubated for 90 min at 308C and then stored at 48C
overnight. Fluorescence per well was then analyzed by using a TECAN
infinite M200 plate reader at 395 nm excitation and an emission wave-
length of 504 nm (25 reads/well, optimal gain, 228C). The data were nor-
malized (I/Imax) and plotted against the compound concentration. Sigmoi-
dal curves were fitted using Hillꢃs equation to yield IC50 values by means
of Origin 7.5 (OriginLab Corporation). Reactions with no inhibitor and
with no DNA template were included as controls.
[19] Other approaches: a) G. Talbot, R. Gaudry, L. Berlinguet, Can. J.
Chem. 1956, 34, 911–914; b) K. Mizusaki, S. Makisumi, Bull. Chem.
Soc. Jpn. 1981, 54, 470–472; c) R. F. W. Jackson, A. Wood, M. J.
Wythes, Synlett 1990, 735–736; d) U. Schmidt, R. Meyer, V. Leiten-
berger, F. Stabler, A. Lieberknecht, Synthesis 1991, 409–413; e) J.
Hꢀusler, Liebigs Ann. Chem. 1992, 1231–1237; f) R. F. W. Jackson,
A. B. Rettie, A. Wood, M. J. J. Wythes, J. Chem. Soc. Perkin Trans. 1
1994, 1719–1726; g) A. Girard, C. Greck, J.-P. Genet, Tetrahedron
Lett. 1998, 39, 4259–4260; h) H. Mues, U. Kazmaier, Synthesis 2001,
0487–0498; i) J. Rudolph, F. Hannig, H. Theis, R. Wischnat, Org.
Lett. 2001, 3, 3153–3155; j) R. Lꢅpine, A.-C. Carbonnelle, J. Zhu,
Synlett 2003, 1455–1458; k) F. Paintner, L. Allmendinger, G.
Bauschke, P. Klemann, Org. Lett. 2005, 7, 1423–1426; l) Y. Shiro, K.
Kato, M. Fujii, Y. Ida, H. Akita, Tetrahedron 2006, 62, 8687–8695;
m) S. K. Pandey, M. Pandey, P. Kumar, Tetrahedron Lett. 2008, 49,
3297–3299.
Acknowledgements
This work was supported in part by the state of NRW (Center for applied
chemical genomics, ZACG), and the Max-Planck-Society (to HW). L.A.
received a Kekulꢅ fellowship from the Fonds der Chemischen Industrie.
H.W. holds an advanced investigator grant from the European Research
Council. We thank Prof. Dr. S. Grond (U Tꢁbingen, Germany) for pro-
viding a sample of kirromycin, and Dr. B. Ellinger (MPI Dortmund) for
conducting bacterial growth inhibition tests.
[20] M. Kaiser, C. Siciliano, I. Assfalg-Machleidt, M. Groll, A. G. Mil-
bradt, L. Moroder, Org. Lett. 2003, 5, 3435–3437.
[21] E. J. Corey, F. Xu and M. Noe, J. Am. Chem. Soc. 1997, 119, 12414–
12415.
[22] a) A. Habel, D. Spiteller, W. Boland, J. Chromatogr. A 2007, 1165,
182–190; b) D. Parker, Chem. Rev. 1991, 91, 1441–1457; c) J. M.
Seco, E. Quinoa, R. Riguera, Chem. Rev. 2004, 104, 17–118. d) M.
Riedrich, S. D. Harkal, M.-D. Arndt, Angew. Chem. 2007, 119, 2755–
2758; Angew. Chem. Int. Ed. 2007, 46, 2701–2703.
[23] T. Ishiyama, M. Murata and N. Miyaura, J. Org. Chem. 1995, 60,
7508–7510.
[24] L. J. Mathias, Synthesis 1979, 561–576.
[25] a) X. Zhang, A. C. Schmitt, W. Jiang, Tetrahedron Lett. 2001, 42,
5335–5338; b) B. Plietker, Synthesis 2005, 2453–2472.
[1] a) K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker, G.-Q. Cao, S.
Barluenga, H. J. Mitchell, J. Am. Chem. Soc. 2000, 122, 9939–9953;
b) K. Ding, Z. Han, Z. Wang, Chem. Asian J. 2009, 4, 32–41.
[2] R. Breinbauer, I. R. Vetter, H. Waldmann, Angew. Chem. 2002, 114,
3002–3015; Angew. Chem. Int. Ed. 2002, 41, 2878–2890.
[3] L. J. Gooßen, G. Deng, L. M. Levy, Science 2006, 313, 662–664.
[4] I. Uchida, N. Shigematsu, M. Ezaki, M. Hashimoto, H. Aoki, H. Im-
anaka, J. Antibiot. 1985, 38, 1462–1468.
[5] J. Schimana, K. Gebhardt, A. Hçltzel, D. G. Schmid, R. Sꢁssmuth, J.
Mꢁller, R. Pukall, H.-P. Fiedler, J. Antibiot. 2002, 55, 565–570.
[6] F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. Hꢀbich,
Angew. Chem. 2006, 118, 5194–5254; Angew. Chem. Int. Ed. 2006,
45, 5072–5129.
[26] J.-Y. Lu, M. Riedrich, M. Mikyna, H.-D. Arndt, Angew. Chem. 2009,
121, 8281–8284; Angew. Chem. Int. Ed. 2009, 48, 8137–8140.
[27] a) H. Loibner, E. Zbiral, Helv. Chim. Acta 1976, 59, 2100; b) O. Mit-
sunobu, Synthesis 1981, 1–28.
[7] M. Paetzel, J. J. Goodall, M. Kania, R. E. Dalbey, M. G. P. Page, J.
Biol. Chem. 2004, 279, 30781–30790.
[8] A. S. Carlstrçm, T. Frejd, J. Chem. Soc. Chem. Commun. 1991,
1216–1217.
[28] M. Sakaitani, Y. Ohfune, J. Org. Chem. 1990, 55, 870–876.
[29] R. D. Firn, C. G. Jones, Nat. Prod. Rep. 2003, 20, 382–391.
[30] a) L. A. Carpino, J. Am. Chem. Soc. 1993, 115, 4397–4398; b) A.
Ehrlich, S. Rotemund, M. Brudel, M. Beyermann, L. A. Carpino, M.
Bienert, Tetrahedron Lett. 1993, 34, 4781–4784; c) L. A. Carpino, A.
El-Faham, F. Albericio, Tetrahedron Lett. 1994, 35, 2279–2282.
[31] S.-g. Kim, J. H. Park, J. Org. Chem. 1988, 53, 3111–3113.
[32] a) F. K. Brown, J. C. Hempel, J. S. Dixon, S. Amato, L. Mueller,
P. W. Jeffs, J. Am. Chem. Soc. 1989, 111, 7328–7333; b) J. C.
Hempel, F. K. Brown, J. Am. Chem. Soc. 1989, 111, 7323–7327;
c) K. Rajamoorthi, D. H. Williams, J. Org. Chem. 1987, 52, 5435–
5437.
[9] a) J. H. Martin, L. A. Mitscher, P. Shu, J. N. Porter, N. Bohonos,
S. E. DeVoe, E. L. Patterson, Antimicrob. Agents Chemother. 1967,
422–425; b) J. H. Martin, J. N. Porter, L. A. Mitscher (Lederle
Pharm.), US 3,452,136, 1969; [Chem. Abstr. 1969, 71, 59640].
[10] a) M. Ezaki, M. Iwami, M. Yamashita, S. Hashimoto, T. Komori, K.
Umehara, Y. Mine, M. Kohsaka, H. Aoki, H. Imanaka, J. Antibiot.
1985, 38, 1453–1461; b) M. Ezaki, N. Shigematsu, M. Yamashita, T.
Komori, K. Umehara, H. Imanaka, J. Antibiot. 1993, 46, 135–140.
[11] I. Uchida, N. Shigematsu, M. Ezaki, M. Hashimoto, H. Aoki, H. Im-
anaka, J. Antibiot. 1985, 38, 1462–1468.
[12] H. C. Wegener, Curr. Opin. Microbiol. 2003, 6, 439–445.
[13] F. Paintner, K. Gçrler, W. Voelter, Synlett 2003, 4, 0522–0526.
[14] R. Endermann, K. Ehlert, S. Raddatz, M. Michels, Y. Cancho-
Grande, S. Weigand, K. Fischer, 2006, DE 102005014247, 52 pp.
[15] H. Waldmann, Y.-P. He, H. Tan, L. Arve, H.-D. Arndt, Chem.
Commun. 2008, 5562–5564.
[33] J. Sandstrçm, Chirality 1995, 7, 181–192.
[34] G. Bringmann, A. J. Price-Mortimer, P. A. Keller, M-J. Gresser, J.
Garner, M. Breuning, Angew. Chem. 2005, 117, 5518–5563; Angew.
Chem. Int. Ed. 2005, 44, 5384–5427.
[35] J. M. Nelson, T. M. Chiller, J. H. Powers, F. J. Angulo, Clin. Infect.
Dis. 2007, 44, 977–980.
[16] a) U. Schmidt, R. Meyer, V. Leitenberger, A. Lieberknecht, H.
Griesser, J. Chem. Soc. Chem. Commun. 1991, 275–277; b) U.
Schmidt, V. Leitenberger, H. Griesser, J. Schmidt, R. Meyer, Synthe-
sis 1992, 1248–1254.
[36] B. Ellinger, Ph.D. thesis, TU Dortmund 2010.
[37] H. R. A. Jonker, S. Baumann, A. Wolf, F. Hiller, S. Schoof, K. W.
Schulte, K. N. Kirschner, H. Schwalbe, H.-D. Arndt, Angew. Chem.
2011, 123, 3366–3370; Angew. Chem. Int. Ed. 2011, 50, 3308–3312.
[17] R. Lꢅpine, J. Zhu, Org. Lett. 2005, 7, 2981–2984.
[18] a) J. Rudolph, F. Hannig, 2002, WO 2002102764, 26 pp; b) T.
Lampe, I. Adelt, D. Beyer, N. Brunner, R. Endermann, K. Ehlert,
H.-P. Kroll, F. von Nussbaum, S. Raddatz, J. Rudolph, G. Schiffer,
A. Schumacher, 2004, DE 10234422, 41 pp; c) R. Endermann, K.
Received: December 17, 2010
Published online: May 4, 2011
1556
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 1546 – 1556