Flexible total synthesis of biphenomycin B

Article abstract of DOI:10.1039/b811583d

A total synthesis of the biaryl antibiotic biphenomycin B is reported which makes use of three independent building blocks (key steps were a clean Suzuki-Miyaura coupling of a free acid iodide, a novel 4-hydroxyornithine synthesis, and a high-yielding macrolactamization); a practical deprotection protocol allowed isolation of the target compound with excellent recovery and purity. The Royal Society of Chemistry.

Full text of DOI:10.1039/b811583d

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Flexible total synthesis of biphenomycin Bw
Herbert Waldmann,*ab Yu-Peng He,ab Hao Tan,ab Lars Arveab and
Hans-Dieter Arndt*ab
Received (in Cambridge, UK) 8th July 2008, Accepted 1st August 2008
First published as an Advance Article on the web 25th September 2008
DOI: 10.1039/b811583d
A total synthesis of the biaryl antibiotic biphenomycin B is
reported which makes use of three independent building blocks
(key steps were a clean Suzuki–Miyaura coupling of a free acid
iodide, a novel 4-hydroxyornithine synthesis, and a high-yielding
macrolactamization); a practical deprotection protocol allowed
isolation of the target compound with excellent recovery and
purity.
Natural products continue to be rich sources of new antibiotic
lead structures.1 The structurally related biarylcyclopeptide
natural products biphenomycin B and A (1, 2)2 and arylomycin
A and B (3, 4)3 represent an interesting case in this regard.
Whilst the 15-membered ring compounds 1 and 2 inhibit protein
biosynthesis with remarkable potency,1 the 14-membered ring
congeners 3 and 4 address the bacterial signal peptidase.4 In
order to enable investigations of this puzzling target dichotomy,
we embarked on a total synthesis of biphenomycin B (Fig. 1).
Fig. 1 Macrocyclic biaryl peptide antibiotics 1–4 and retrosynthetic
To allow for broad variability of this newly projected
synthesis,5 it was planned to assemble 1 from three fully
functionalized building blocks which can be individually
varied. In a retrosynthetic sense, 1 could arise from a hydroxy-
ornithine and an amino-acid derived biaryl, which was
envisioned to be formed by a mild Suzuki–Miyaura coupling
of suitable aromatic precursors.
disconnections of biphenomycin B (1).
Amino acid 6 was prepared from benzyl bromide 56 in
496% ee using the asymmetric glycine enolate alkylation
technology of Corey et al. (Scheme 1).7 Boc-group and methyl-
ester introduction and Pd0-mediated borylation8 delivered
boronate 7 in excellent yield. Cbz-protection of 6 provided
iodide 8, which could be directly coupled to 7 under Pd0
catalysis9 to give biaryl acid 9 without protecting the free
carboxylic acid. No epimerization was observed under
optimized conditions (74% yield). In contrast, attempts at
coupling the free acid of 7 with an ester derived from 6
remained unsuccessful.
The central hydroxyornithine amino acid10 was elaborated
from commercially available trans-4-hydroxyproline 10
(Scheme 2). 10 was N-Boc protected, smoothly converted to
the tBu ester using O-tert-butyl isourea11 and silylated to
provide the TBS ether 11. Pyrrolidine 11 was subjected to a
Scheme 1 Synthesis of biaryl building block 9. Reagents and condi-
tions: (a) Ph2CQGlyOtBu, O-allyl-N-(9-anthracenylmethyl)cinchoni-
dinium bromide (10 mol%), CsOH (10 equiv.), CH2Cl2, À50 1C, 24 h;
then 4 M HCl in dioxane, 86%, 96% ee; (b) Boc2O (1.5 equiv.), 2 M
NaOH (2 equiv.), dioxane/H2O (1 : 1), 16 h, 92%; (c) MeI (1.5 equiv.),
K2CO3 (2 equiv.), acetone, 56 1C, 16 h, 97%; (d) (pinB)2 (1.2 equiv.),
PdCl2(dppf) (5 mol%), KOAc (3 equiv.), DMSO, 80 1C, 16 h, 96%; (e)
CbzCl (1.2 equiv.), Na2CO3 (1.5 equiv.), dioxane/H2O (1 : 1), 16 h,
74%; (f) 7 (1.2 equiv.), Pd(OAc)2 (20 mol%), P(o-tolyl)3 (40 mol%),
Cs2CO3 (3 equiv.), dioxane/H2O (9 : 1), 80 1C, 16 h, 74%. Pin =
pinacolato, dppf = bis-diphenylphosphinoferrocene.
a Technische Universitat Dortmund, Fakultat Chemie, Otto-Hahn-Str.
6, D-44227 Dortmund, Germany
¨
¨
b Max-Plank-Institut fur Molekulare Physiologie, Otto-Hahn-Str. 11,
D-44227 Dortmund, Germany.
¨
E-mail: hans-dieter.arndt@mpi-dortmund.mpg.de;
Fax: +49(0)231-1332498
w Electronic supplementary information (ESI) available: Character-
ization data for 6, 9, 14, 17, and l. See DOI: 10.1039/b811583d
regioselective a-oxidation with cat. RuO4 to cleanly give pyro-
glutamate 12 (89%),12 which could be regioselectively ring
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Scheme
2 Protected hydroxyornithine synthesis. Reagents and
conditions: (a) Boc2O (1 equiv.), NaOH (1.2 equiv.), THF/H2O
(2 : 1), 16 h, 93%; (b) O-tert-butyl N,N-diisopropylisourea (2 equiv.),
THF, 60 1C, 16 h, 68%; (c) TBSCl (1.2 equiv.), DMAP (0.1 equiv.),
imidazole (2.6 equiv.), 16 h, 94%; (d) RuO2ÁnH2O (25 mol%), NaIO4
(3 equiv.), EtOAc/H2O (1 : 2), 16 h, 89%; (e) NaBH4 (5 equiv.),
MeOH/NaPi buffer (1 : 1, pH = 7.0), 0 1C - RT, 8 h, 62%; (f)
PPh3 (3 equiv.), DIAD (3 equiv.), HN3 (5 equiv.), 4 h, 87%; (g)
TBSOTf (1.5 equiv.), 2,6-lutidine (2 equiv.), CH2Cl2, 15 min, then
TBAF (1 equiv.), THF/H2O (10 : 1), 70%.
opened to alcohol 13 in buffered MeOH (62%). Alcohol 13 was
converted to azido amine 14 in a two step sequence involving a
Mitsunobu reaction with hydrazoic acid13 and selective
Boc-group cleavage with TBSOTf14 (61%, 20% from 10).
Biaryl acid 9 was then coupled to amine 14 under standard
conditions (78%, Scheme 3), and the resulting dipeptide 15 was
simultaneously Boc- and tBu-deprotected with TESOTf15 in
remarkable yield and selectivity. Ring closure to the macro-
lactam 17 was then achieved with excellent results using HATU/
HOAt16 under pseudo-high dilution conditions (75%).
The protecting groups on 17 had been initially chosen to
allow orthogonal deprotection17 for future derivatizations, but
to liberate biphenomycin B (1) all of them had to be removed.
It was found that the OTBS and azido functions in 17 would
react under the strongly Lewis-acidic conditions necessary to
cleave the phenylmethyl ethers. Therefore, deprotection
commenced with reducing the azide to the amine (PMe3)
under basic conditions with concomitant methyl ester cleavage
in quantitative yield.
Scheme 3 Completion of the total synthesis of biphenomycin B (1).
Reagents and conditions: (a) EDCÁHCl (1.5 equiv.), HOBt
(1.5 equiv.), EtN(iPr)2 (2.2 equiv.), CH2Cl2, 16 h, 78%; (b) TESOTf
(20 equiv.), 2,6-lutidine (40 equiv.), CH2Cl2, 6 h, quant.; (c) slow
addition to HATU (1.5 equiv.), HOAt (1.5 equiv.), EtN(iPr)2
(2.2 equiv.), CH2Cl2, 30 h, 75%; (d) PMe3 (9 equiv., 1 M in toluene),
THF/0.1 M NaOH (9 : 1), 8 h, quant.; (e) 1 M HCl, 16 h, quant.; (f)
BBr3 (1 M in CH2Cl2, 20 equiv.), 24 h, 52% (prep. HPLC). EDC =
N-ethyl-N-dimethylaminopropyl carbodiimide; HOBt = 1-hydroxy-
benzotriazole; HATU
hexafluorophosphate; HOAt = 7-aza-1-hydroxybenzotriazole.
=
7-aza-1-hydroxybenzotriazoluronium
Funding by the Deutsche Forschungsgemeinschaft
(Emmy-Noether young investigator grant to H.D.A.), the
Fonds der Chemischen Industrie (graduate fellowship to
L.A.), the Max-Planck society (to H.W.), and the state of
Nordrhein-Westfalen (ZACG Dortmund) was appreciated.
Aqueous HCl was subsequently used to remove the TBS
group. The resulting 2-amino alcohol could then be treated
with an excess of BBr3, which cleanly cleaved the Cbz and
OMe groups. In unprotected form the side chain now proved
to be inert, presumably due to in situ protection as a cyclic
boronate. Serendipitously, under these conditions the product
precipitated from the reaction mixture, which allowed easy
removal of all excess reagent. The recovered crude product
was desalted and further purified by prep. HPLC, which
provided synthetic biphenomycin B (1) in 52% yield from
17, in all aspects (1H, 13C, IR, mp, HRMS, [a]D) matching the
data reported for the natural product.1,5
Notes and references
1 Review: F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand and
D. Habich, Angew. Chem., Int. Ed., 2006, 45, 5072.
¨
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R. Meyer and H. Griesser, J. Chem. Soc., Chem. Commun., 1992,
In summary, we report a streamlined and flexible total
synthesis of biphenomycin B which provides the target molecule
in high purity in only 11 steps and 14% yield from benzyl
bromide 5. Importantly, in contrast to previous syntheses,
stereochemical and structural variations in all three amino acid
subunits can be liberally accessed. These results will significantly
facilitate exploiting biphenomycin B and its biarylpeptide
natural product scaffold.
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(e) T. C. Roberts, P. A. Smith, R. T. Cirz and F. E. Romesberg,
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