The first synthesis of promothiocin A

Article abstract of DOI:10.1039/a805762a

The first total synthesis of the naturally occurring macrocyclic thiopeptide promothiocin A 1 is described.

Full text of DOI:10.1039/a805762a

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The first synthesis of promothiocin A
Christopher J. Moody*† and Mark C. Bagley
School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
The first total synthesis of the naturally occurring macro-
cyclic thiopeptide promothiocin A 1 is described.
CO2Me
Me
H2N
N
i, ii
Promothiocin A 1, isolated from Streptomyces sp. SF2741, is a
member of the thiopeptide family of antibiotics.1 These natural
products, which inhibit protein synthesis in bacteria, 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, little synthetic work has been carried out
to date, although the synthesis of the pyridine fragments of the
micrococcins, sulfomycin and nosiheptide has been ad-
dressed,2–5 and very recently micrococcin P has yielded to
synthesis.6 In continuation of our interest in the synthesis of
heterocyclic natural products,7 we now report the first total
synthesis of promothiocin A 1, thereby confirming the structure
and stereochemistry.
The structure of promothiocin A 1 was established by NMR
spectroscopy, although the stereochemistry of the natural
product was not reported.1 Therefore we have assumed that the
three stereocentres result from natural amino acids (see Fig. 1)
and could be incorporated from suitable derivatives of
(S)-alanine and (S)-valine. The overall plan, indicated by the
arrows in Fig. 1, was to form the macrocycle by two peptide
coupling reactions (1 and 2), followed by introduction of the
dehydroalanine side chain (3).
The starting point was the synthesis of the two oxazoles 2 and
3 from (S)-alanine and glycine, respectively. This was readily
achieved using our previously published method;8 thus rho-
dium(ii) acetate catalysed reaction of the N-protected amino
acid amides with methyl 2-diazo-3-oxobutanoate resulted in
clean insertion of the metallocarbenoid into the amide N–H
bond. Cyclodehydration of the resulting keto amides using the
Wipf protocol (Ph3P, I2, Et3N)9 gave the required oxazoles 2
and 3 in 56 and 49% overall yield respectively (Scheme 1). The
glycine derived oxazole 3 was deprotected to give the
2-aminomethyloxazole 4 for subsequent coupling, whereas the
alanine derived oxazole 2 was converted into the oxazole-
thiazole-pyridine fragment 5 using our previously developed
O
O
R
R
NHP
NHP
iv
2 R = Me, P = Boc
3 R = H, P = Z
4 R = P = H
iii
CH2OBn
N
N
EtO2C
S
Me
N
O
5
Me
NHBoc
Scheme 1 Reagents and conditions: i, methyl 2-diazo-3-oxobutanoate cat.
Rh2(OAc)4, CHCl3, heat (80% for 2, 76% for 3); ii, Ph3P, I2, Et3N, CH2Cl2
(70% for 2, 64% for 3); iii, H2, Pd-C, MeOH (100%); iv, see ref. 10
method,10 based on the Bohlmann–Rahtz pyridine synthe-
sis.11
The lower valine-oxazole-thiazole fragment 9 was obtained
as shown in Scheme 2. Thus N-Boc-valine was coupled to the
aminomethyloxazole 4 in high yield by mixed anhydride
methodology using isobutyl chloroformate and N-methylmor-
pholine (NMM) to give the oxazole 6. The alanine derived
thiazole 7 was obtained from the known N-Boc derivative,
prepared using the modified Hantzsch reaction,12 the standard
conditions leading to extensive racemisation, and coupled to the
carboxylic acid derived by hydrolysis of the ester 6 to give the
valine-oxazole-thiazole 8 in excellent yield (Scheme 2). Finally
Me
Me
Me
NHBoc
i
HN
Me
NHBoc
NHP
O
HO2C
Me
N
O
CO2Me
CO2Et
ii, iii
Me
HN
Me
6
O
N
CO2Et
N
N
H
N
O
H2N
S
S
Me
O
Me
Me
iv
7
8
9
P = Boc
R = H
Scheme 2 Reagents and conditions: i, BuiO2CCl, NMM, THF, then 4
(87%); ii, LiOH, aq. THF (93%); iii, BuiO2CCl, NMM, THF then 7 (84%);
iv, AcCl, EtOH (100%)
Fig. 1 Promothiocin A 1 and proposed disconnections
Chem. Commun., 1998
2049

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deprotection of the N-terminal Boc group with ethanolic HCl
gave the free amine 9 for subsequent coupling.
The coupling of the lower and upper fragments of the
promothiocin macrocycle was achieved using mixed anhydride
methodology (Scheme 3). Hydrolysis of the ester group in the
oxazole-thiazole-pyridine 5 was followed by activation with
isobutyl chloroformate/NMM and coupling with the amine 9 to
give the terminally protected ‘linear peptide’ 10 in good yield.
Although there are several methods available for macro-
lactamisation, we have found the Schmidt protocol,13 used in
our recent synthesis of nostocyclamide,7 to be particularly
reliable. Hence the ester group in 10 was hydrolysed and
converted into the corresponding pentafluorophenyl ester by
coupling with pentafluorophenol in the presence of 1-(3-di-
methylaminopropyl)-3-ethylcarbodiimide
hydrochloride
(EDCI). The pentafluorophenyl ester was not purified but
underwent deprotection at the N-terminus on treatment with
HCl in dioxane. Work-up and treatment with triethylamine
resulted in lactamisation to give the promothiocin macrocycle
11 in 55% yield. The synthesis was completed by elaboration of
the dehydroalaninamide side chain, although these final steps
proved far from trivial. Deprotection of the benzyl ether to give
the pyridine-2-methanol derivative 12 was followed by conver-
sion to the aldehyde 13 using o-iodoxybenzoic acid (IBX) in
DMSO,14 and further oxidation with sodium chlorite15 to give
the desired acid 14. Coupling of the acid 14 with the tert-
butyldimethylsilyl ether of (S)-serinamide using EDCI gave the
amide 15; deprotection of the serine side-chain with TBAF was
followed by dehydration (MsCl, Et3N) to give promothiocin A
1 (Scheme 3). The synthetic material had 400 MHz 1H and 100
MHz 13C NMR spectra identical to those reported for the natural
product,1 and its specific rotation of [a]2D3 + 87.3 (c 0.34,
CHCl3–MeOH, 1:1) [lit.,1 +79.2 (c 0.69, CHCl3–MeOH, 1:1)]
strongly implies that the natural product does indeed have the
stereochemistry indicated in Fig. 1. Thus we have completed the
first total synthesis of the thiopeptide promothiocin A 1, and
established the stereostructure of the natural product.
We thank the EPSRC and the Leverhulme Trust for support
of our research, Claire Hesketh for preliminary experiments,
and Dr Vladimir Sik for detailed NMR experiments.
Notes and References
† E-mail: c.j.moody@ex.ac.uk
1 B.-S. Yun, T. Hidaka, K. Furihata and H. Seto, J. Antibiot., 1994, 47,
510.
2 T. R. Kelly, C. T. Jagoe and Z. Gu, Tetrahedron Lett., 1991, 32, 4263;
T. R. Kelly and F. Lang, J. Org. Chem., 1996, 61, 4623.
3 K. Okumura, M. Shigekuni, Y. Nakamura and C.-G. Shin, Chem. Lett.,
1996, 1025.
4 M. A. Ciufolini and Y. C. Shen, J. Org. Chem., 1997, 62, 3804.
5 K. Umemura, H. Noda, J. Yoshimura, A. Konn, Y. Yonezawa and
C.-G. Shin, Tetrahedron Lett., 1997, 38, 3539.
6 C.-G. Shin, K. Okumura, M. Shigekuni and Y. Nakamura, Chem. Lett.,
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601.
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Perkin Trans. 1, 1998, 591.
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10 C. J. Moody and M. C. Bagley, Synlett, 1998, 361.
11 F. Bohlmann and D. Rahtz, Chem. Ber., 1957, 90, 2265.
12 M. W. Bredenkamp, C. W. Holzapfel, R. M. Snyman and W. J. vanZyl,
Synth. Commun., 1992, 22, 3029; E. Aguilar and A. I. Meyers,
Tetrahedron Lett., 1994, 35, 2473.
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Scheme 3 Reagents and conditions: i, LiOH, aq. THF (94%); ii, BuiO2CCl,
NMM, THF, then 9 (69%); iii, LiOH, aq. THF (97%); iv, C6F5OH, EDCI,
CH2Cl2 (100%); v, 4 m HCl in dioxane, then aq. KHCO3; vi, Et3N, CHCl3
(55% over 2 steps); vii, BCl3·SMe2, CH2Cl2 (39%); viii, IBX, DMSO
(81%); ix, NaClO2, KH2PO4, 2-methylbut-2-ene, aq. ButOH (70%); x,
O-TBDMS-serinamide, EDCI, CH2Cl2 (50%); xi, TBAF, THF (57%); xii,
MsCl, Et3N, CH2Cl2, then Et3N (59%)
Received in Cambridge, UK, 23rd July 1998; 8/05762A
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Chem. Commun., 1998