Total Synthesis of Nosiheptide

Article abstract of DOI:10.1002/anie.201603140

Total synthesis of the bismacrocyclic thiopeptide antibiotic nosiheptide was achieved through the assembly of a fully functionalized linear precursor followed by consecutive macrocyclizations. Key features are a critical macrothiolactonization and a mild deprotection strategy for the 3-hydroxypyridine core. The natural product was identical to isolated authentic material in terms of spectral data and antibiotic activity.

Full text of DOI:10.1002/anie.201603140

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603140
German Edition: DOI: 10.1002/ange.201603140
Natural Product Synthesis
Total Synthesis of Nosiheptide
K. Philip Wojtas, Matthias Riedrich, Jin-Yong Lu, Philipp Winter, Thomas Winkler,
Sophia Walter, and Hans-Dieter Arndt*
Abstract: Total synthesis of the bismacrocyclic thiopeptide
antibiotic nosiheptide was achieved through the assembly of
a fully functionalized linear precursor followed by consecutive
macrocyclizations. Key features are a critical macrothiolacto-
nization and a mild deprotection strategy for the 3-hydroxy-
pyridine core. The natural product was identical to isolated
authentic material in terms of spectral data and antibiotic
activity.
In designing a synthesis of nosiheptide, the electrophilic
dehydroalanine (DHA) residue and thiol precursors of the
potentially labile thioester were deemed incompatible
(Figure 1). Therefore, the DHA residue was initially
masked as a protected serine derivative (a). The thioester
was traced back (b) to an w-mercapto acid with acid-labile
protection (Dpm, Tr). Further disconnections at strategic
amide bonds (c/d) led to the fragments 7 and 8, which feature
sets of matching orthogonal protecting groups, guided by the
successful macrolactamization precedence toward the A-ring
model.[9] Introducing the indole ester into fragment 7 early
seemed appropriate, since late-stage esterifications have been
found to be problematic.[9] While the synthesis of hydroxy-
pyridine 8 was known,[9b] fragment 7 was to be assembled
from a thiazole peptide (9–11), hydroxymethyl indole 12, and
g-lactam 13.
T
hiopeptide antibiotics are highly potent and structurally
complex secondary metabolites from soil bacteria (Actino-
mycetes),[1] and they are formed by ribosomal peptide
biosynthesis.[2] Total syntheses have been reported for several
examples of monomacrocyclic thiopeptide natural products,[3]
as well as for the bismacrocyclic thiopeptides thiostrepton[4]
and its close relative siomycin.[5] Other bismacrocyclic
thiopeptide antibiotics have remained a challenge, notably
the highly active “class e” scaffolds[1] of nosiheptide (1),
nocathiacin (2–5), and glycothiohexide (6, Figure 1). Nosi-
heptide (1) contains a unique 3-hydroxypyridine core, several
substituted thiazoles, a sterically hindered aromatic B-ring
thiolactone, and an indolylmethyl ester, all embedded within
a bismacrocyclic scaffold endowed with a pendant dehydroa-
minoacid side chain. The other congeners (2–6) feature an
additional transannular bridge further dividing ring B, as well
as oxidative modifications, methylations, and glycosidations.
In the nocathiacins, one Cys residue is apparently exchanged
for a Ser, as indicated by a sulfur-free B-ring macrolactone.
Nosiheptide (1) can be regarded as the structural proto-
type of the class e thiopeptide antibiotics.[6] It exerts excep-
tional antibiotic activity in vitro and in a mouse model against
critical Gram-positive pathogens such as MRSA, VRE, or
Clostridium difficile.[6c] Chiefly due to unfavorable physico-
chemical properties, it has been used previously only for
applications in farm animals, mainly as a feed additive.[7]
Previous synthetic work on nosiheptide has focused on
building blocks and the development of synthetic methods.[8]
The characteristic A-[9] and B-ring[10] systems have been
synthesized in model studies. Herein, we report on a successful
total synthesis of nosiheptide that was achieved by employing
double macrocyclization of a fully functionalized linear
precursor.
Initially, indole derivative 12 was prepared from 3-nitro-2-
methylbenzylalcohol (14, Scheme 1), which was O-THP-
Scheme 1. Synthesis of indole 12. Reagents and conditions: a) Dihy-
dropyran (2 equiv), PPTS (0.1 equiv), 1,2-dichloroethane, 208C, 18 h;
b) NaH (3 equiv), diethyloxalate (6 equiv), DMF, 08C!208C, 18 h;
c) dimethylmethylidene-iminium chloride (3 equiv), NEt3 (3 equiv),
208C, 13 h; d) cat. 10% Pd/C (10 wt%), 1–4 bar H2, 4 ꢀ molecular
sieves (20 wt%), THF/iPrOH (1:1), 18 h; e) aq. NaOH (2.5m, 3 equiv),
EtOH, reflux, 30 min; f) AcOH (70%), 208C, 18 h; g) diphenyldiazo-
methane, cat. TFA, THF, 608C, 3 h; h) butyric anhydride (2 equiv),
EtNiPr2 (4 equiv), DMAP (0.1 equiv), THF, 08C!208C, 13 h.
protected and C-acylated with diethyl oxalate[11] to give a-
keto ester 15 (99% yield, two steps). Methenylation[12] gave
nitroarylenone 16 (99%), which was reductively transformed
into indole 17. Incomplete reduction to the N-hydroxy
indole[13] could be suppressed by employing optimized hydro-
genation conditions. Then the ethyl ester was exchanged for
an acid-labile Dpm group (!18!12, 56%).[9b] To test the
stability of esters of 12 and to find suitable deprotection
conditions, model butyrate 19 was investigated (Scheme 1).
Indeed, standard conditions (TFA in CH2Cl2) led to unselec-
tive cleavage and steady loss of butyrate even at low TFA
concentrations (1%). In the event, by using BF3 in AcOH[14]
[*] Dipl.-Chem. K. P. Wojtas, Dr. M. Riedrich, Dr. J.-Y. Lu, Dr. P. Winter,
M. Sc. T. Winkler, M. Sc. S. Walter, Prof. Dr. H.-D. Arndt
Friedrich-Schiller-Universitꢁt
Institut fꢂr Organische Chemie und Makromolekulare Chemie
Humboldtstrasse 10, 07743 Jena (Germany)
E-mail: hd.arndt@uni-jena.de
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603140.
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Figure 1. Chemical structures of class e thiopeptide natural products and retrosynthetic disconnection of nosiheptide. All=Allyl, Alloc=Allylox-
ycarbonyl, Boc=tert-Butyloxycarbonyl, DBU=1,8-Diazabicyclo[5.4.0]undec-7-en, DMAP=Dimethylaminopyridine, Dpm=Diphenylmethyl, Fmoc=
Fluorenylmethyloxycarbonyl, HATU=O-(7’-Azabenzotriazol-1’-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, HOAt=1-Hydroxy-7-azabenzo-
triazole, PPTS=Pyridinium 4-methylphenylsulfonate, PyAOP=(7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate,
PyDOP=(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-3-yl)oxytripyrrolidinophosphonium hexafluorophosphate, TBS=tert-Butyldimethylsilyl, TIPS=Triiso-
propylsilyl, Tr=Triphenylmethyl, Ts=4-Methylphenylsulfonyl.
or by buffering TFA in anisole as a solvent,[15] selective
cleavage of the Dpm group was achieved.
In order to incorporate the indole into the nosiheptide
structure, alcohol 12 was acylated with activated lactam 13[9]
under carefully controlled basic conditions (89%, Scheme 2).
Tce ester 20 was reductively deprotected (82% yield), and the
resulting acid 21 was extended with azido thiol 22 and
transformed into thiazole 23 by using an aza-Wittig ring
closure and thiazoline oxidation (86%).[16] Liberation of the
amino group in 23 proved challenging owing to the high acid
sensitivity of the indolyl ester and a propensity for g-
butyrolactam formation. However, chemoselective conver-
Scheme 2. Synthesis of the indole-thiazole building block. Reagents and conditions: a) 12 (0.5 equiv), NaH (1.25 equiv), THF, ꢀ788C, 2 h (98%
b.r.s.m.); b) Zn (36 equiv), 1m KH2PO4, THF, 458C, ultrasound, 10 h (95% b.r.s.m.); c) 22 (1.5 equiv), PyAOP (1.2 equiv), EtNiPr2 (2.5 equiv),
08C!208C, 3 h; d) PPh3 (1.5 equiv), THF, ꢀ208C!208C, 2 h; then 408C, 14 h; e) DBU (2.1 equiv), BrCCl3 (1.05 equiv), CH2Cl2, ꢀ208C, 1 h;
f) TBSOTf (11 equiv), 2,6-lutidine (22 equiv), CH2Cl2, 08C!208C; g) 10 or 11 (1 equiv), HATU (1.4 equiv), HOAt (6.5 equiv), NaHCO3 (3 equiv),
THF, 08C!208C, 48 h; h) DBU (5% in CH2Cl2), ꢀ208C, 5 min. b.r.s.m.=based on recovered starting material.
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sion of the Boc group into a silyl carbamate was achieved by
ful. Substrate 30 then was cleanly S-detritylated and O-Dpm-
using TBSOTf.[17] We found that TBS carbamate 24 could be
directly coupled to thiazole acid fragments 10 or 11 (see the
Supporting Information) by using HATU/HOAt and solid
NaHCO3, which apparently releases the amine from the TBS
carbamate slowly in situ. Coupling products could thereby be
obtained in good yields (39–71%). Interestingly we found
that silyl-protected threonine residues induced sensitivity to
E/Z isomerization of the enamine double bond under basic
conditions, while the N-acyl enamine had been rather inert in
building blocks featuring a tBu protecting group.[9] This
feature was more prominent with larger groups (TIPS >
TBS @ tBu). An excess of DBU at low temperature was
found to be optimal to cleanly achieve Fmoc cleavage (!7,
95%).
Closure of the B-ring assembly was then tested after Pd-
mediated deallylation[18] of ester 25 (Scheme 3). Coupling of
amine 27 to the resulting acid led to an amide that had to be
Tr- and Dpm-deprotected. Under acidic conditions, partial
cleavage of the indolyl ester and/or loss of the TBS groups
became apparent. However, TFA in anisole gave clean
conversion into an w-mercapto carboxylic acid that was
consecutively cyclized to thiolactone 28 in 66% yield. These
experiments validated the protecting-group strategy and set
the stage for completion of the synthesis. Notably, it was
found that the TBS group on the threonine residue was rather
labile toward acids and fluoride, therefore, the more stable
TIPS derivative was subsequently used instead.
deprotected by applying the conditions established earlier.
The annelated macrothiolactone B-ring was effectively
formed with PyAOP in THF (!31, 43%).
In order to install the terminal DHA residue, the primary
TIPS ether on scaffold 31 was selectively removed by using
aqueous HF. For the dehydration of the terminal serine
amide, a variety of conditions and reagents (e.g., TsCl/DMAP,
Tf2O, PPh3/CCl4, CuICl/EDCI) were tested to induce elimi-
nation. Concomitantly, dehydration of the terminal amide
(nitrile formation), Ts-deprotection, and/or 3-hydroxypyri-
dine refunctionalization were frequently observed. To our
delight, O-sulfonylation of the monodesilylated compound
could be selectively achieved by using MsCl and 2,6-lutidine.
Carefully monitored treatment with DBU then induced
elimination to generate the crucial DHA residue (!32, ca.
70%, 35% after preparative HPLC). Further desilylation was
then realized by using Et3N·3HF. The concluding cleavage of
the O-Ts group was then achieved by exposing compound 33
to a solution of HOBT in DMF in the presence of base.
Notably, the Ts group was removed cleanly without compro-
mising the thioester bond. Synthetic nosiheptide (1) was then
purified by employing preparative TLC (ca. 65%) followed
by preparative HPLC (36% yield over two steps).
Although mass spectrometry and optical rotation meas-
urements of the final product 1 indicated structural identity,
we found the NMR spectra of nosiheptide to be quite
dependent on solvent mixture, water content, and pH. To
exclude ambiguities, a comparison with original material was
pursued. The natural product was isolated for this purpose
from a commercial feeding additive containing nosiheptide
(“1% premix”) by following published procedures.[20] Com-
parison of HPLC, NMR, and LC–MS data for the synthetic
compound 1 with those for the synthesized material unequiv-
ocally confirmed structural identity (see the Supporting
Information).
Moreover, an initial activity evaluation in inhibition-zone
tests showed that the isolated and synthetic material similarly
inhibited the growth of Streptomyces coelicolor, with appar-
ent minimum inhibitory concentration (MIC) values of 0.3 mm
in each case (see the Supporting Information). This result
demonstrates that nosiheptide also displays potent antibacte-
rial activity against soil bacteria, very close relatives and
congeners of the producer S. actuosus. Surprisingly, O-
tosylation of the hydroxypyridine core is not tolerated, since
compound 33 did not display any appreciable antibacterial
activity. These results are currently being further investigated
with pathogenic bacteria.
Scheme 3. Completion of the fully equipped B-ring model. Reagents
and conditions: a) [Pd(PPh3)4] (20 mol%), PhSiH3 (8.6 equiv), THF,
08C, 20 min, 93%; b) PyBOP (2.1 equiv), EtNiPr2 (2.5 equiv), 27
(1.5 equiv), DMF, 08C!208C, 16 h, 77%; c) anisole/TFA/Et3SiH
(8:5:4), ꢀ258C!08C, 24 h; d) PyAOP (1.2 equiv), EtNiPr2 (2.2 equiv),
THF, 08C, 15 min, 208C, 1 h, 66%.
In conclusion, a viable total synthesis of the bicyclic
thiopeptide antibiotic nosiheptide was developed that enables
access to unique class e thiopeptide scaffolds. Key features
are an optimized macrocyclization precursor setup and an
advanced protecting-group strategy adapted to the specific
liabilities of the nosiheptide structure. Since this synthesis
allows the exchange of building blocks, we anticipate that
a deeper chemical biology profiling of this highly potent and
structurally surprising antibiotic by chemical synthesis will
now be possible.
Amine 7 had now to be coupled with acid 8 to obtain the
fully assembled linear precursor 29 (Scheme 4). During these
experiments, we found that the Ts protection of the hydroxy-
pyridine was partially cleaved when HOBt or HOAt were
used in excess. After screening coupling reagents, clean
conversion and an excellent coupling yield of 93% were
achieved by using PyDOP.[19] Pd-mediated Alloc and allyl
deprotection and consecutive macrocyclization of the A-ring
by using HATU under highly dilute conditions were success-
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Scheme 4. Completion of the synthesis. Reagents and conditions: a) PyDOP (2 equiv), EtNiPr2 (2.2 equiv), THF, 08C, 15 min, 208C, 2 h;
b) [Pd(PPh3)4] (20 mol%), PhSiH3 (20 equiv), THF, 08C, 30 min; c) HATU (5 equiv), EtNiPr2 (30 equiv), THF, 08C, 15 h; d) anisole/TFA/Et3SiH
(8:5:4), ꢀ208C, 30 min; then 08C, 4 h; e) PyAOP (1.2 equiv), EtNiPr2 (2.3 equiv), THF, 08C, 15 min, then 208C, 15 h; f) CH3CN/conc. HF (24:1),
08C, 25 h, 75% (90% b.r.s.m.); g) methanesulfonyl chloride (100 equiv), 2,6-lutidine/CH2Cl2 (1:10), 08C!208C, 0.5 h; h) DBU (2% in CH2Cl2),
ꢀ788C!ꢀ358C, 4.5 h (35%, two steps); i) Et3Nꢃ3HF/THF (1:9), 08C!208C, 27 h; j) HOBt (10 equiv), EtNiPr2 (7 equiv), DMF, 08C ! 208C,
1.5 h. Pyr=pyrrolidine-1-yl.
121, 670 – 732; total syntheses after 2009, micrococcin P1: c) D.
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Received: March 30, 2016
Published online: && &&, &&&&
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Communications
Natural Product Synthesis
Each ring is different: A total synthesis of
the bismacrocyclic thiopetide antibiotic
nosiheptide was achieved through the
assembly of a fully functionalized linear
precursor, followed by consecutive mac-
rocyclizations. Key to success were the
late-stage formation of a dehydroalanine
residue and finely tuned deprotection of
the hydroxypyridine core. The synthesis
product was identical to the natural
material in terms of structure and func-
tion.
K. P. Wojtas, M. Riedrich, J.-Y. Lu,
P. Winter, T. Winkler, S. Walter,
H.-D. Arndt*
&&&& — &&&&
Total Synthesis of Nosiheptide
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