Studies on thiopeptide antibiotics: Aynthesis of an oxazole-thiazole-pyridine fragment related to promothiocin A

Full text of DOI:10.1055/s-1998-1670

LETTERS
361
Studies on Thiopeptide Antibiotics: Synthesis of an Oxazole-Thiazole-Pyridine Fragment
related to Promothiocin A
Christopher J. Moody and Mark C. Bagley
Department of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, U.K.
Fay +44(1392)263434; E-mail c.j.moody@exeter.ac.uk
Received 4 December 1997
Promothiocin A 1, isolated from Streptomyces sp. SF2741, is a member
1
of the thiopeptide family of antibiotics. These antibiotics, which inhibit
protein synthesis in bacteria and induce the expression of various genes
(of unknown function), are characterised by their complex structure in
which an array of heterocyclic rings is incorporated into a macrocyclic
peptide framework. Despite the fascinating biological activity of the
thiopeptide antibiotics, very little synthetic work has been carried out to
date, although the synthesis of the pyridine fragments of the
micrococcins, sulfomycin and nosiheptide has been addressed
2-5
6,7
recently, as has the construction of some related pyridines.
In
continuation of our interest in the synthesis of heterocyclic natural
8
products, we now report the synthesis of the oxazole-thiazole-pyridine
2, which contains the required functionality for elaboration into
promothiocin A 1.
Scheme 1
chloroformate, and reaction with magnesium ethyl malonate. This
method was more effective than related procedures using imidazolide
With the exception of Ciufolini’s recent synthesis of the heterocyclic
core of the micrococcins, in which the pyridine ring is assembled from
two fragments which are combined to give a 1,5-diketone precursor for
14
intermediates. Reaction of 8 with ammonium acetate in benzene-
15,16
acetic acid then gave the enamine 4 in 85% yield (Scheme 2),
4
subsequent reaction with ammonia and dehydrogenation, most
although an increase in the amount of acetic acid and ammonium acetate
15
approaches to related heterocycles rely on the stepwise modification of
pre-formed pyridine rings. Our plan, outlined in Scheme 1, was to
construct the pyridine 3 by reaction of the enamine 4 with the ynone 5.
This method of pyridine formation (enamine plus ynone), first reported
over and above the literature conditions was necessary for complete
conversion. The key pyridine forming step was carried out by heating
17
the enamine 4 with ynone 5 in ethanol at 50 °C overnight to effect the
initial conjugate addition, followed by removal of the solvent and
heating the residue at 140 °C under vacuum to effect cyclisation. This
9
by Bohlmann and Rahtz 40 years ago, has found little or no use to date,
18
and although it is related to the corresponding reactions with enones and
hence to the well known Hantzsch pyridine synthesis, it has the
considerable advantage in that the aromatic product is formed directly.
resulted in a good yield of the desired pyridine 3, establishing for the
first time that the Bohlmann-Rahtz method can be used for the synthesis
of relatively complex pyridines.
With the pyridine-3-ester 3 in hand, the thiazole ring was elaborated
Since the stereochemistry of the natural product was not reported, we
have assumed that the stereocentres derive from “natural” L-aminoacids
and therefore the synthesis of the pyridine 2 started from a derivative of
L(S)-alanine. N-Boc-Alaninamide 7 was converted into the chiral
19
using the modified Hantzsch reaction,
the standard procedure
resulting in a complex mixture of products. Hydrolysis of the ester
(92%), was followed by amide formation (85%), and conversion into
the thioamide (59%) which was reacted with ethyl bromopyruvate and
potassium hydrogen carbonate in THF at 0 °C followed by treatment
with TFAA in the presence of 2,6-lutidine to give the oxazole-thiazole-
10
oxazole 6 using our previously published method; thus rhodium(II)
catalysed reaction of 7 with methyl diazoacetoacetate resulted in clean
insertion of the metallocarbenoid into the amide N-H bond (80%).
Cyclodehydration of the resulting keto-amide using the Wipf protocol
20
pyridine 2, containing all the necessary functionality for elaboration
11
12,13
into the natural product.
(Ph P, I , Et N) gave the required oxazole 6 in 70% yield.
To
3
2
3
prepare the required enamine 4 necessitated homologation of the
oxazole ester 6 to the corresponding β-ketoester 8; thus hydrolysis of
the ester 6 (95%) was followed by mixed anhydride formation wth ethyl

362
LETTERS
SYNLETT
Soc., Perkin Trans. 1 1997, 2405.
(9) Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265.
(10) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J.; Slawin, A.
M. Z. Synlett 1996, 825.
(11) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(12) The rhodium(II) catalysed N-H insertion and subsequent
cyclodehydration reactions were carried out as described in
reference 10.
(13) (S)-Methyl 2-[1-(tert-Butoxycarbonyl)aminoethyl]oxazole-4-car-
22
boxylate 6, mp 94-95 °C (from ether-light petroleum); [α] = -
D
-1
44.0° (c 1.0 in CHCl ); ν
(KBr)/cm 3357, 1719, 1689; δ
3
max
H
(400 MHz; CDCl ) 5.18 (1 H, bs, exch D O, NH), 4.92 (1 H, m,
3
2
CH), 3.89 (3 H, s, MeO), 2.59 (3 H, s, Me), 1.51 (3 H, d, J 7.0,
CHMe), and 1.42 (9 H, s, CMe ); the optical purity was confirmed
3
as >99% by HPLC on a chiral stationary phase (Chiralpak AD,
hexane : 2-propanol, 9 : 1, 1.0 ml/min) by comparison with the
racemate.
(14) Bram, G.; Vilkas, M. Bull. Soc. Chim. Fr. 1964, 945; Houghten,
R. A.; Simpson, R. A.; Hanson, R. N.; Rapoport, H. J. Org. Chem.
1979, 44. 4536.
(15) Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902.
(16) (S)-Ethyl 3-Amino-3-{2-[1-(tert-butoxycarbonyl)aminoethyl]-
oxazol-4-yl}propenoate 4, colourless needles, mp 103-104 °C
22
(from ether-light petroleum); [α]
= -60.5° (c 1.1 in CHCl );
3
D
-1
ν
(KBr)/cm 3455, 3351, 1681, 1669; δ (400 MHz; CDCl )
max
H
3
6.92 (2 H, bs, exch D O, NH ), 5.09 (1 H, bs, exch D O, NH),
2
2
2
4.89 (1 H, m, CHMe), 4.83 (1 H, m, CH), 4.16 (2 H, q, J 7.1,
CH Me), 2.49 (3 H, s, Me), 1.51 (3 H, d, J 7.0, CHMe), 1.45 (9 H,
2
s, CMe ), and 1.29 (3 H, t, J 7.1, CH Me).
3
2
(17) Prepared by addition of ethynylmagnesium bromide to
benzyloxyacetaldehyde in THF (86%), followed by oxidation to
the ketone with o-iodoxybenzoic acid (IBX) in DMSO (89%). For
oxidations with IBX, see: Frigerio, M.; Santagostino, M.
Tetrahedron Lett. 1994, 35, 8019.
(18) (S)-Ethyl 2-{2-[1-(tert-Butoxycarbonyl)aminoethyl]oxazol-4-yl}-
6-(benzyloxy)methylpyridine-3-carboxylate 3, pale yellow foam;
22
-1
Scheme 2
[α]
= -21.4° (c 0.6 in CHCl ); ν
(CHCl )/cm 3442, 1715;
max 3
D
3
δ
(400 MHz; CDCl ) 7.96 (1 H, d, J 8.0, 4-H), 7.48 (1 H, d, J
3
H
8.0, 5-H), 7.41-7.27 (5 H, m, ArH), 5.23 (1 H, d, J 7.2, exch D O,
2
Acknowledgements
NH), 4.94 (1 H, m, CH), 4.72 (2 H, s, PyCH ), 4.66 (2 H, s,
2
We thank the E.P.S.R.C. for support of this work under the ROPA
Scheme.
PhCH ), 4.31 (2 H, q, J 7.1, CH Me), 2.56 (3 H, s, Me), 1.52 (3 H,
2
2
d, J 6.9, CHMe), 1.45 (9 H, s, CMe ), and 1.28 (3 H, t, J 7.1,
3
CH Me).
2
References and Notes
(19) Bredenkamp, M. W.; Holzapfel, C. W.; Snyman, R. M.; vanZyl,
W. J. Synth. Commun. 1992, 22, 3029; Aguilar, E.; Meyers, A. I.
Tetrahedron Lett. 1994, 35, 2473.
(1) Yun, B.-S.; Hidaka, T.; Furihata, K.; Seto, H. J. Antibiot. 1994,
47, 510.
(2) Kelly, T. R.; Jagoe, C. T.; Gu, Z. Tetrahedron Lett. 1991, 32,
4263; Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623.
(20) (S)-2-{2-[1-(tert-Butoxycarbonyl)aminoethyl]oxazol-4-yl}-3-(4-
ethoxycarbonylthiazol-2-yl)-6-(benzyloxy)methylpyridine 2, pale
23
-1
(3) Okumura, K.; Shigekuni, M.; Nakamura, Y.; Shin, C. G. Chem.
Lett. 1996, 1025.
yellow oil; [α]
= -26.8° (c 1.3 in CHCl ); ν
(CHCl )/cm
max 3
D
3
3437, 1715; δ (400 MHz; CDCl ) 8.35 (1 H, d, J 8.1, 4-H), 8.17
H
3
(1 H, s, SCH), 7.61 (1 H, d, J 8.1, 5-H), 7.41-7.26 (5 H, m, ArH),
5.09 (1 H, bs, exch D O, NH), 4.89 (1 H, m, CH), 4.76 (2 H, s,
(4) Ciufolini, M. A.; Shen, Y. C. J. Org. Chem. 1997, 62, 3804.
2
(5) Umemura, K.; Noda, H.; Yoshimura, J.; Konn, A.; Yonezawa, Y.;
PyCH ), 4.67 (2 H, s, PhCH ), 4.42 (2 H, q, J 7.2, CH Me), 2.26
2
2
2
Shin, C. G. Tetrahedron Lett. 1997, 38, 3539.
(3 H, s, Me), 1.46 (3 H, d, J 6.8, CHMe), 1.43 (9 H, s, CMe ), and
3
(6) Patt, W. C.; Massa, M. A. Tetrahedron Lett. 1997, 38, 1297.
1.40 (3 H, t, J 7.2, CH Me); δ (100.6 MHz; CDCl ) 165.4 (C),
2
C
3
(7) Umemura, K.; Watanabe, K.; Ono, K.; Yamaura, M.; Yoshimura,
162.9 (C), 161.3 (C), 160.2 (C), 154.9 (C), 154.8 (C), 148.6 (C),
147.1 (C), 138.9 (CH), 137.7 (C), 132.6 (C), 128.9 (CH), 128.5
(CH), 127.9 (CH), 127.8 (CH), 127.6 (C), 120.2 (CH), 79.8 (C),
J. Tetrahedron Lett. 1997, 38, 4811.
(8) Moody, C. J.; Bagley, M. C. Synlett 1996, 1171; Moody, C. J.;
Lightfoot, A. P.; Gallagher, P. T. J. Org. Chem. 1997, 62, 746;
Miah, S.; Moody, C. J.; Richards, I. C.; Slawin, A. M. Z. J. Chem.
73.1 (CH ), 72.7 (CH ), 61.5 (CH ), 44.7 (CH), 28.3 (Me), 20.3
2
2
2
(Me), 14.3 (Me), and 11.1 (Me).