First synthesis of an amythiamicin pyridine cluster

Article abstract of DOI:10.1039/b310944e

The pyridine-containing central domain of the amythiamicin group of thiopeptide antibiotics is prepared in protected form in 9 steps, 93% ee and 18% overall yield from (S)-2-[1-(tert-butoxycarbonylamino)-2-methylpropyl] thiazole-4-carboxylic acid by Michael addition-cyclodehydration of a 2-(2-thiazolyl)enamine and 1-(2-thiazolyl)propynone.

Full text of DOI:10.1039/b310944e

First synthesis of an amythiamicin pyridine cluster†
Mark C. Bagley,*a James W. Dale,a Robert L. Jenkinsa and Justin Bowerb
a School of Chemistry, Cardiff University, PO Box 912, Cardiff, UK CF10 3TB. E-mail: bagleymc@cf.ac.uk;
Fax: +44 29 20874030; Tel: +44 29 20874029
b Vernalis, Granta Park, Abington, Cambridge, UK CB1 6GB
Received (in Cambridge, UK) 9th September 2003, Accepted 14th November 2003
First published as an Advance Article on the web 25th November 2003
The pyridine-containing central domain of the amythiamicin
group of thiopeptide antibiotics is prepared in protected form in
9 steps, 93% ee and 18% overall yield from (S)-2-[1-(tert-
butoxycarbonylamino)-2-methylpropyl]thiazole-4-carboxylic
acid by Michael addition–cyclodehydration of a 2-(2-thiazol-
yl)enamine and 1-(2-thiazolyl)propynone.
a macrocyclic thiopeptide that contains a heterocyclic ensemble of
heavily modified amino acids centred about a polythiazolylpyridine
core. Although no route to amythiamicin A has appeared in the
literature, the synthesis of other thiopeptide antibiotics and their
heterocyclic components has attracted considerable international
interest, resulting in the total synthesis of micrococcin P13 and
promothiocin A.4 At this time the configuration of three of the five
stereogenic centres present in amythiamicin is not known but, as a
working hypothesis, it was assumed that they were derived from the
The amythiamicins1 are members of the thiopeptide class of
antibiotics, a family of sulfur-containing highly modified cyclic
peptides isolated for their effectiveness against methicillin resistant
Staphylococcus aureus (MRSA).2 Structurally, amythiamicin A is
more common -amino acids based on degradation studies on the
L
structurally related antibiotic GE2270A (MDL 62,879).5
As part of our interest in the discovery of new heteroannulation
methods for the synthesis of pyridines,6,7 we set out to establish a
rapid route to the heterocyclic core of the amythiamicins by
Michael addition–cyclodehydration of enamine 2 and alkynone 3
that would proceed with total control of regiochemistry and
generate the pyridine heterocycle in the correct oxidation state
(Scheme 1). Central to our strategy was the need to minimise
subsequent manipulation following the heteroannulation reaction,
facilitated by the use of 1-(2-thiazolyl)propynone 3, anticipated to
be highly reactive and to require an unusual Bohlmann–Rahtz
procedure in order for efficient cyclization to the target pyridine 1.
Although a simpler 1-(2-thiazolyl)propynone has been used before
in a Bohlmann–Rahtz reaction with an enamine this required a five-
fold excess of reagent, limiting its use as a method to access
pyridines substituted at C-6.4 We sought to validate a more efficient
and rapid route to these pyridines and, in so doing, facilitate the
synthesis of the amythiamicin central heterocyclic domain with
suitable functionality for elaboration of the natural product.
The first component, 1-(2-thiazolyl)propyn-1-one 3, was pre-
pared in five steps (Scheme 2) from 2,2-diethoxyacetamide (4) by
thionation with phosphorus pentasulfide, Hantzsch thiazole synthe-
Scheme 2 Synthesis of 1-(2-thiazolyl)propyn-1-one 3.
Table 1 Methods for the synthesis of model pyridine 10
Entry
Substrate
Conditions
Yielda (%)
1
2
3
4
5
9
3
3
8
9
Neat, 150 °C, 4 h
80
30
35
33
> 98
Toluene–ZnBr2, reflux, 2 h
Toluene–AcOH, 50 °C, 2 h
Toluene–AcOH, MnO2, 50 °C, 5 h
Toluene–AcOH, 50 °C, 1.5 h
Scheme 1 Synthetic approach to the central amythiamicin domain 1.
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b3/b310944e/
a Isolated yield after purification on silica.
102
C h e m . C o m m u n . , 2 0 0 4 , 1 0 2 – 1 0 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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sis with ethyl bromopyruvate in ethanol in the presence of 4 Å
molecular sieves, followed by acid catalysed acetal deprotection to
give aldehyde 7 that could be stored at room temperature. Addition
of ethynylmagnesium bromide in THF with aqueous work up and
subsequent oxidation of propargylic alcohol 8 with manganese(IV
)
oxide gave propynone 3. As anticipated, this substrate proved
unstable at room temperature and so was generated from aldehyde
7 as required. In order to establish new heteroannulation conditions
suitable for this substrate, propynone 3 was reacted with ethyl b-
aminocrotonate by a variety of different methods (Table 1) to give
model pyridine 10 substituted at C-6 in accordance with the target
amythiamicin domain. When dienone 9, generated by Michael
addition in ethanol at 50 °C, was heated to 150 °C (entry 1)
cyclodehydration to pyridine 10 was incomplete and so alternative
conditions were sought. Acid catalysed one-step procedures failed
to give satisfactory yields (entries 2, 3), as did tandem oxidation–
heteroannulation8 of propargylic alcohol 8 (entry 4) and so we
investigated a new cyclodehydration method, hitherto reported only
as an aside in the development of one-step acid-catalysed
Bohlmann–Rahtz procedures.6 Dienone 9, generated by Michael
addition in ethanol, was stirred at 50 °C in toluene–acetic acid to
give pyridine 10 in > 98% yield (entry 5).
With successful conditions established in a model system for
rapid introduction of the C-6 substituent, efforts were directed
towards establishing the group at C-3 with similar rapidity.
Hantzsch thiazole 11 was reduced with lithium aluminium hydride
to give alcohol 12, which was protected as 2-(trimethylsilyl)-
ethoxy-methyl (SEM) ether 13 (Scheme 3). Directed 5-lithiation
with n-butyllithium and reaction with chlorotrimethylsilane pro-
vided thiazole 14 as a protected pyridine C-3 building block for the
synthesis of amythiamicin.
Scheme 4 Reagents and conditions: (i) EtO2CCl, THF, Et3N then aq. NH3;
(ii) LR; (iii) NaHCO3, ethyl bromopyruvate then trifluoroacetic anhydride,
2,6-lutidine; (iv) LiOH, H2O, MeOH; (v) EtO2CCl, THF, Et3N then
HN(Me)OMe·HCl; (vi) 14, n-BuLi; H2O; (vii) TBAF, THF, RT, 1 h; (viii)
NH4OAc, mwave, 120 °C (100 W), PhMe, 30 min; (ix) 3, EtOH, 60 °C;
toluene–AcOH, 70 °C.
domain 1 with total regiocontrol in 85% yield and 93% ee. This
work represents the first synthesis of this heterocyclic cluster, in
protected form, generated in only 9 steps and 18% overall yield
from 15, and constitutes a rapid route to the amythiamicin antibiotic
family.
N-Protected -valine was transformed to valine-derived thiazole
L
15 by the modified Hantzsch procedure of Meyers,9 followed by
hydrolysis. Reaction with ethyl chloroformate under basic condi-
tions, aminolysis of the mixed anhydride with aqueous ammonia
and thionation of amide 16 using Lawesson’s reagent (LR) gave
thioamide 17 (Scheme 4). Hantzsch thiazole synthesis with ethyl
bromopyruvate under basic conditions followed by hydroxythiazo-
line dehydration, using a mixture of trifluoroacetic anhydride and
2,6-lutidine, gave chiral bis-thiazole 18 in 96% ee [HPLC on
Chiralpak AD]. Hydrolysis with lithium hydroxide, formation of
Weinreb amide 20 and reaction with the lithio-derivative of
2-methylthiazole 14 gave Claisen condensation product 21.
Protodesilylation using tetrabutylammonium fluoride in THF
followed by microwave irradiation of thiazole 22 and ammonium
acetate in toluene at 120 °C provided enamine 2 for submission to
the key Bohlmann–Rahtz reaction. Utilizing conditions successful
for the synthesis of model pyridine 10, Michael addition of enamine
2 and propynone 3 in ethanol followed by acetic acid-catalysed
cyclodehydration at 70 °C, gave the amythiamicin heterocyclic
Notes and references
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7 M. C. Bagley, J. W. Dale, D. D. Hughes, M. Ohnesorge, N. G. Phillips
and J. Bower, Synlett, 2001, 1523; M. C. Bagley, R. Lunn and X. Xiong,
Tetrahedron Lett., 2002, 43, 8331; M. C. Bagley, J. W. Dale and J.
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Scheme 3 Synthesis of thiazole building block 14.
9 E. Aguilar and A. I. Meyers, Tetrahedron Lett., 1994, 35, 2473.
C h e m . C o m m u n . , 2 0 0 4 , 1 0 2 – 1 0 3
103