Aza-wittig-supported synthesis of the a ring of nosiheptide

Article abstract of DOI:10.1002/anie.200903477

An array of aza-Wittig reactions: In the unique synthesis of the A ring of the potent thiopeptide antibiotic nosiheptide, mild aza-Wittig thiazole ring closure, a ScIII-mediated regioselective ester hydrolysis, and a highly efficient macrolactam formation

Full text of DOI:10.1002/anie.200903477

Angewandte
Chemie
DOI: 10.1002/anie.200903477
Natural Products
Aza-Wittig-Supported Synthesis of the A Ring of Nosiheptide**
Jin-Yong Lu, Matthias Riedrich, Martin Mikyna, and Hans-Dieter Arndt*
In the constant quest for lead molecules to combat infectious
diseases,[1] a promising class of natural products not used for
human therapy are the thiopeptide antibiotics.[2] These
heterocycle-rich molecules are biosynthesized from linear
ribosomal peptides[3] and block the biosynthesis of the
bacterial protein very efficiently.[2,4] The bismacrocyclic
nosiheptide (1; Scheme 1) stands out among them as having
the highest potency against multidrug-resistant S. aureus
(MRSA) strains.[4d,5,6] Derivatives of 1 with improved biolog-
ical properties have been identified,[7] but most synthetic
studies have focused on the preparation of small frag-
ments.[8,9] Notably, a study on the thioester-containing B-
ring of 1 was recently reported.[10] Herein, we describe the
synthesis of the fully functionalized A ring of 1 by using aza-
Wittig transformations.[11,12]
Nosiheptide (1) is distinguished from other thiopeptide
natural products[2] by an indolic acid macrothiolactone group
which forms the smaller B ring (“southern hemisphere”),[10]
and by a peculiar 3-hydroxypyridine group in the larger
A ring (“northern hemisphere”).[10] Retrosynthetic discon-
nection of the indole 3[8d] (I, II) and introduction of latent
functionality and protecting groups leads to the A-ring
Scheme 1. Retrosynthetic analysis of nosiheptide (1) by thioesterifications (I/II), macrolactam formation (III/IV) and aza-Wittig ring closures (V,
VIII, IX; rings in bold); Bn=benzyl, Boc=tert-butoxycarbonyl, Fmoc=9-fluorenylmethyloxycarbonyl, TBS=tert-butyldimethylsilyl, TIPS=triisopro-
pylsilyl, Tf=trifluormethylsulfonyl, Tr=triphenylmethyl, Ts=4-toluenesulfonyl.
scaffold 2 as a key synthetic target. We sought to disconnect
[*] M. Sc. J.-Y. Lu,[+] Dr. M. Riedrich,[+] Dipl.-Chem. M. Mikyna,
the A ring into three fragments (III, IV, V): The thiazole
Dr. H.-D. Arndt
segment 4, the 3-hydroxypyridine core 5, and the dipeptide
Technische Universitꢀt Dortmund, Fakultꢀt Chemie
side chain 6. Compound 4 should be available from two
smaller building blocks (VI), and elimination of a side chain
could deliver the enamide (VII). We have shown before that
1-azadiene cycloadditions efficiently furnish functionalized 3-
hydroxypyridines such as 5.[13] The dipeptide 6 is easily
available.[14] Overall, three aza-Wittig ring closures (V, VIII,
IX) were planned for introducing the thiazole rings. In this
synthesis design we planned to make ideal use of the mild aza-
Wittig reaction, which is an acid- and base-free kinetic
condensation reaction mediated by an intermediate imino-
phosphorane [Eq. (1)].[11,12] Liberal selection of the heteroa-
tom (X = O, S, NR)[12] as well as the degree of oxidation in the
ring (4,5-H2 or 4,5-D)[12] would offer additional flexibility.
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
and
Max-Planck-Institut fꢁr molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
Fax: (+49)231-133-2498
E-mail: hans-dieter.arndt@mpi-dortmund.mpg.de
[+] Both authors contributed equally to this work.
[**] Our work was supported by the DFG (AR493-1,-2) and the Fonds der
Chemischen Industrie (H.-D.A.). J.-Y.L. was a member of the IMPRS
Chemical Biology. We thank Dr. M. Schꢁrmann and Dr. H. Preut for
the X-Ray crystal structure analysis and Prof. Dr. H. Waldmann for
continuous support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903477.
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Communications
The synthesis began with trans-4-hydroxyproline
7
(Scheme 2), which was protected at the nitrogen atom by a
Boc group and then transformed under Mitsunobu condi-
tions[15] into the crystalline bicyclic lactone 8 with an inverted
Scheme 3. Preparation of bisthiazole peptide 21. Reagents and condi-
tions: a) TFA/CH2Cl2 (1:1), 0!208C, 1 h; b) Fmoc(tBu)ThrOH, EDC,
HOBt, CH2Cl2/DMF (10:1), 0!208C, 4 h; c) o-NO2C6H4SeCN
(2 equiv), PBu3 (2 equiv), CH2Cl2, 208C, 16 h; d) 1% H2O2, 208C,
30 min; e) [Pd(PPh3)4], PhSiH3 (2 equiv), CH2Cl2, 208C, 10 min; f) 15,
HOBt, EDC, 0!208C, 5 h; g) 1% DBU, 5% piperidine in CH2Cl2, 08C,
30 min; h) 50% TFA, 0!208C, 20 min.
mediated deallylation under neutral reaction conditions[18]
then provided acid 20, which was coupled to amine 15 and
delivered segment 4 (58%). Removal of the Fmoc group
provided amine 21, which was ready for extension (96%).
The hydroxypyridine core was elaborated by a hetero-
Diels–Alder cycloaddition.[13] The regiochemistry was
unequivocally established by X-ray crystal structure analysis
of ketone 22,[14] which was then converted into bisthiazolyl
pyridine 5 by a racemization-free Hantzsch annelation
(Scheme 4).[13a] The hydrolysis of diester 5 initially proved
nonselective under a variety of reaction conditions. We found,
Scheme 2. Synthesis of thiazole amine 15. Reagents and conditions:
a) Boc2O, 10% K2CO3, 1,4-dioxane, 0!208C, 8 h; b) diisopropylazodi-
carboxylate (1.1 equiv), PPh3 (1 equiv), THF, 08C, 4 h; c) TceOH
(4 equiv), NaH, THF, ꢀ788C, 1 h; d) TBSCl, DMF, 208C, 6 h; e) RuCl3
(1 mol%), NaIO4 (3 equiv), CCl4/CH3CN/H2O (1:9:15), 08C, 8 h;
f) BnOH, NaH, THF, ꢀ788C; g) Zn0, THF, NaH2PO4 (20 mm, pH 7.0),
ultrasound, 16 h; h) EDC, HOBt, 13, CH2Cl2, 08C, 2 h; i) PPh3, THF,
ꢀ20!208C, 4 h; j) BrCCl3, DBU, CH2Cl2, 4 h; k) TFA/CH2Cl2, 1:2, 08C,
30 min. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMF=N,N-dime-
thylformamide, EDC=N-ethyl-N’-(3-dimethylaminopropyl)carbodi-
imide, HOBt=1-hydroxybenzotriazole, Tce=trichloroethyl, THF=
tetrahydrofuran, TFA=trifluoroacetic acid.
[19]
however, that catalytic amounts of Sc(OTf)3 removed the
methyl ester group on the pyridine ring selectively if a free
hydroxy group at C3 was present (23!24).[20] The synthesis
was initially carried on with the mandatory[13a] Boc-protected
thioaminal group, but all attempts to unmask the cysteine
residue at a later stage in the synthesis were unsuccessful.
Therefore, the thioaminal 24 had to be cleaved at this stage.
The free thiol was captured with TrCl, and an Alloc group was
introduced on the nitrogen atom (!25, 82%).
configuration (62%). Compound 8 was transesterified with
TceOH, protected with a TBS group (!9, 69%), and
regioselectively oxidized to lactam 10 (76%) using a catalytic
amount of RuO4.[16] Ring opening of 10 was achieved with
NaOBn at low temperature (87%). The resulting orthogo-
nally protected 4-hydroxyglutamate 11 was converted into
acid 12 by reduction with Zn0. Thioester formation with
azidothiol 13,[12] aza-Wittig ring closure with PPh3, and
oxidation delivered building block 14 in excellent yield and
purity (79%, d.r. > 98:2), which was swiftly converted into the
labile amine 15 by removal of the protecting groups.
Furthermore, threonine 16 was converted into thiazole 17
by using an aza-Wittig reaction (89%; Scheme 3).[12] Removal
of the tBu and Boc groups and subsequent selective chain
extension at the nitrogen atom was carried out on Fmoc-
protected Thr using EDC/HOBt (!18, 99%). We found that
the crucial enamide could be cleanly installed by using the
method developed by Grieco et al. (!19, 90%).[17] In
contrast, activation of the OH group (Ms, Ts) and elimination
(DBU, DMAP) gave 19 with inferior results. Palladium-
To install the side chain, the hydroxy acid 25 was activated
with phosgene and treated with peptide thiol 6, which was
prepared in situ from the stable peptide 26 (5% TFA, quant.).
Immediate aza-Wittig ring closure gave the thiazoline, which
was directly oxidized to the tris-thiazolyl pyridine 27 (46%,
over 4 steps). Protection of the hydroxy group at C3 using a
sulfonate group had to be carefully controlled (!28, 80%
based on recovered starting material), then acid 29 was
released using Me3SnOH.[21] Coupling of 29 to amine 21
proved challenging under many reaction conditions, but
reliable transformation into 30 was achieved with DEPBT
as the activating reagent (87%; 47% after preparative
HPLC).[22] Parallel removal of the allyl-based protecting
groups could then be cleanly achieved—despite the sulfur-
rich substrate 30—with Pd0/PhSiH3 under neutral reaction
conditions (99%).
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Scheme 4. Synthesis of peptide 31. Reagents and conditions: a) (Bu4N)OH (2 equiv), 1,4-dioxane, 208C, 5 min; b) Sc(OTf)3 (5 mol%), 1,4-
dioxane/H2O (3:1), pH 8.5, 608C, 8 h; c) TFA/CH2Cl2/Et3SiH (13:13:1), 208C, 30 min; d) TrCl, DMF, 208C, 14 h; e) AllocCl, NaHCO3, THF/H2O
(5:1); f) COCl2 (20 % in toluene, 1.1 equiv), NEt3, THF, ꢀ408C, 2 h; then 6 (1.2 equiv), DMAP (0.1 equiv); g) PPh3, THF, ꢀ20!408C, 20 h;
h) BrCCl3, DBU, CH2Cl2, ꢀ20!208C, 2 h; i) TsCl, NEt3, DMAP (0.1 equiv), CH2Cl2, 08C, 2 h; j) Me3SnOH (9 equiv), 1,2-dichloroethane, 808C, 4 h;
k) DEPBT (3 equiv), NaHCO3 (10 equiv), THF, 21, 208C, 19 h; l) PhSiH3, [Pd(PPh3)4], CH2Cl2. Alloc=allyloxycarbonyl, DEPBT=3-(diethoxyphos-
phoryloxy)-1,2,3-benzotriazin-4(3H)-one, DMAP=4-dimethylaminopyridine.
The stage was now set for formation of the macrolactam
(Scheme 5). In the event, HATU proved to be a superb
mediator of this ring-closing reaction,[23] but excess HOAt had
to be minimized to avoid the formation of side products. The
slow addition of amino acid 31 in nonpolar solvent gave the
best results and consistently delivered the fully functionalized
A ring 2 in excellent yield (82%; 56% after preparative
HPLC). Notably, other cyclization strategies were less
productive (data not shown), thus suggesting a very favorable
conformational preorganization of 31.
Preliminary deprotection studies of 2 showed that the
thiol group could be cleanly unmasked (!33; Scheme 5).
Alkylation delivered the stable thioether 34. The silyl and tBu
groups could be removed under standard reaction conditions
(HF/pyridine, 30% TFA), with removal of the TIPS group
being the most labile. Removal of the TFA-stable Ts group
was achieved in parallel to base-mediated cleavage of the Bn
ester group (32). These results indicate that the A-ring
scaffold 2 is suited well for access to nosiheptide (1) and its
derivatives.
In summary, an efficient synthesis to the fully function-
alized A Ring of nosiheptide (1) was presented. En route we
have demonstrated that aza-Wittig ring closures allow chal-
lenging thiopeptide functionality to be mastered. A novel
ScIII-mediated regioselective ester hydrolysis, highly efficient
formation of a macrolactam, and manipulation strategies for
the A ring featuring the unique 3-hydroxypyridine nucleus
have been developed. These results will prove highly valuable
Scheme 5. Manipulation of the A ring 2. Reagents and conditions:
a) HATU, EtNiPr2, CH2Cl2/DMF (18:1), slow addition of 31 (0.8 mm
final concentration); b) Et3SiH, TFA/CH2Cl2 (1:19); c) NaOH (0.35m)
in CH2Cl2/MeOH (1:3); d) ICH2CONH2, DMF. HOAt=1-hydroxy-7-
for the efficient synthesis of thiopeptides such as nosihep-
azabenzotriazole, HATU=O-(7’-azabenzotriazol-1’-yl)-1,1,3,3-tetrame-
thyluronium hexafluorophosphate.
tide,[5,7] and thus facilitate their further exploration.
Angew. Chem. Int. Ed. 2009, 48, 8137 –8140
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Communications
Received: June 26, 2009
Published online: September 25, 2009
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Keywords: antibiotics · aza-Wittig reactions · heterocycles ·
.
natural products · thiopeptides
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