Synthesis and establishment of stereochemistry of the unusual polyoxazole-thiazole based cyclopeptide YM-216391 isolated from Streptomyces nobilis

Article abstract of DOI:10.1039/b416530f

A concise total synthesis of the unusual oxazole-based cyclopeptide structure YM-216391, which also establishes the stereochemistry of the natural product i.e. 1, is described. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b416530f

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Synthesis and establishment of stereochemistry of the unusual
polyoxazole–thiazole based cyclopeptide YM-216391 isolated from
Streptomyces nobilis
Jon Deeley and Gerald Pattenden*
Received (in Cambridge, UK) 28th October 2004, Accepted 19th November 2004
First published as an Advance Article on the web 23rd December 2004
DOI: 10.1039/b416530f
A concise total synthesis of the unusual oxazole-based
cyclopeptide structure YM-216391, which also establishes the
stereochemistry of the natural product i.e. 1, is described.
The unusual polyoxazole–thiazole-based cyclopeptide 1, desig-
nated YM-216391, was recently isolated from Streptomyces
nobilis.1 It shares both a structural and biological homology with
the potent telomerase inhibitor telomestatin
2 which is
showing promise in cancer chemotherapy.2 The structure of
YM-216391 comprises a continuum of five azoles which have their
origins in serine, cysteine and phenylalanine, linked via a glycine–
valine–isoleucine tripeptide tether. The complete stereochemical
assignment of YM-216391 has not been established. In this
communication we describe a concise total synthesis of the
cyclopeptide, which not only confirms its unique structure
but also allows the assignment of its stereochemistry, shown in
formula 1.
Thus, the 2,4-disubstituted oxazoles
3 and 4 and the
trisubstituted oxazole 5 were first elaborated from their constituent
amino acids using methodology which is well-precedented in the
literature.3 A coupling reaction between 3 and 4 in the presence of
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(EDC), 1-hydroxybenzotriazole (HOBt) and 4-methylmorpholine
(NMM)4 next led to the amide 6 which was then converted into
the trisoxazole 8a, via 7, in three straightforward steps (Scheme 1).
Saponification of 8a, followed by coupling the resulting carboxylic
acid 8b with the oxazole substituted amine 5 (EDC, HOBt, NMM;
87%) next led to the tetraoxazole amide 9. The amide 9 was then
*gp@nottingham.ac.uk
Scheme 1 Reagents and conditions: i, EDC, HOBt, NMM, CH2Cl2, 0 uC A rt, 24 h, 56%; ii, H2, 20% Pd(OH)2/C, MeOH–THF (2 : 1), rt, 81%; iii,
DAST, CH2Cl2, 278 uC, 1.5 h; iv, BrCCl3, DBU, CH2Cl2, 0 uC A rt, 24 h, 57% over two steps; v, NaOH, THF, H2O, rt, 24 h, 88%.
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Scheme 2 Reagents and conditions: i, EDC, HOBt, NMM, CH2Cl2, 0 uC A rt, 24 h, 87%; ii, Lawesson’s reagent, THF, reflux, 18 h, 50%; iii, 4.0 M HCl
solution in dioxane, rt, 24 h, 91%; iv, EDC, HOBt, NMM, CH2Cl2, 0 uC A rt, 48 h, 68%; v, NaOH, THF, H2O, rt, 24 h; vi, 4.0 M HCl solution in dioxane,
rt, 18 h, 65% over two steps.
Scheme 3 Reagents and conditions: i, HATU, NMM, CH2Cl2–DMF (2:1), 0 uC A rt, 72 h, 88%; ii, DAST, CH2Cl2, 278 uC, 2 h, 88%; iii, MnO2,
CH2Cl2, rt, 48 h, 27%.
converted into the corresponding thioamide 10, using Lawesson’s
reagent,5 which was then deprotected leading to the amine
hydrochloride salt 11 (Scheme 2).
CH2Cl2 at 278 uC, which then underwent oxidation in the
presence of MnO2 at room temperature to produce the YM-
216391 structure with the stereochemistry shown in formula 17.
Comparison of the 1H NMR spectroscopic data for synthetic 177
with those recorded for natural YM-216391, showed that although
there were close similarities, the two structures were not identical.
We surmised that the two structures differed in their stereo-
chemistry at the valine residue, and that the natural product was
most likely derived from D- rather than L-valine. Accordingly, we
re-synthesised the dipeptide 12 using D-valine and L-isoleucine (cf.
18), and then reproduced the sequence of reactions, shown in
Schemes 2 and 3, producing the cyclopeptide intermediate 20,
which differs from 15 only according to its stereochemistry at the
isopropyl bearing carbon centre (Scheme 4). Conversion of the
intermediate 20 into the thiazoline 21, followed by oxidation with
MnO2 in CH2Cl2 then gave the cyclopeptide 1, whose NMR
Believing that the tripeptide tether in naturally occurring YM-
216391 had its origins in the ‘natural’ amino acids L-isoleucine and
L-valine, the azole-based amine 11 was next condensed with the
protected dipeptide 12 derived from L-isoleucine and L-valine
leading to the advanced precursor 13. The methyl ester and the
N-Boc protecting groups in 13 were then removed, in sequence,
producing the amino acid 14, which underwent smooth macro-
lactamisation in the presence of O-(7-azabenzotriazol-1-yl)-
N,N,N9,N9-tetramethyluronium hexafluorophosphate (HATU)4a,6
and NMM at 0 uC to room temperature leading to the
cyclopeptide 15 in an agreeable 88% yield (Scheme 3). Finally,
the thioamide unit in 15 was converted into the corresponding
thiazoline 16 using (diethylamino)sulfur trifluoride (DAST) in
798 | Chem. Commun., 2005, 797–799
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Scheme 4 Reagents and conditions: i, EDC, HOBt, NMM, CH2Cl2, 0 uC A rt, 48 h, 82%; ii, NaOH, THF, H2O, rt, 24 h; iii, 4.0 M HCl solution in
dioxane, rt, 18 h, 70% over two steps; iv, HATU, NMM, CH2Cl2–DMF (2:1), 0 uC A rt, 72 h, 75%; v, DAST, CH2Cl2, 278 uC, 2 h, 89%; vi, MnO2,
CH2Cl2, rt, 48 h, 55%.
spectroscopic data8 were identical to those described for the
Lett., 2002, 43, 2459–2461; D. C. Palmer, Oxazoles: Synthesis,
Reactions, and Spectroscopy, Part A, John Wiley & Sons, Inc.
Hoboken, New Jersey, 2003.
4 (a) S. V. Downing, E. Aguilar and A. I. Meyers, J. Org. Chem., 1999,
64, 826–831; (b) A. Bertram and G. Pattenden, Heterocycles, 2002, 58,
521–561.
5 O. E. Jensen and A. Senning, Tetrahedron, 1986, 42, 6555–6564;
M. P. Cava and M. I. Levinson, Tetrahedron, 1985, 41, 5061–5087;
G. Lajoie, F. Le´pine, L. Maziak and B. Belleau, Tetrahedron Lett., 1983,
24, 3815–3818; K. Clausen, M. Thorsen and S.-O. Lawesson,
Tetrahedron, 1981, 37, 3635–3639.
6 T. Hu and J. S. Panek, J. Am. Chem. Soc., 2002, 124, 11368–11378;
K. J. Hale, J. Cai and G. Williams, Synlett., 1998, 149–152.
7 dH (500 MHz, DMSO-d6) 9.15 (1H, s), 9.05 (1H, s), 8.95 (1H, s), 8.71
(1H, s), 8.58 (1H, d, J 5 8.4 Hz), 8.47 (2H, d, J 5 7.1 Hz), 8.47–8.40
(1H, m), 7.98 (1H, d, J 5 5.6 Hz), 7.62–7.49 (3H, m), 5.13 (1H, dd,
J 5 17.2 and 8.9 Hz), 4.68 (1H, dd, J 5 8.4 and 5.5 Hz), 4.20–4.08 (2H,
m), 2.18–2.07 (1H, m), 2.06–1.98 (1H, m), 1.68–1.53 (1H, m), 1.29–1.13
(1H, m) and 1.02–0.71 (12H, m) ppm.
8 Synthetic YM-216391 (1): [a]2D0 –56 (c 5 0.50, CHCl3); dH (500 MHz,
DMSO-d6) 9.12 (1H, s), 9.02 (1H, s), 8.93 (1H, s), 8.71 (1H, dd, J 5 9.1
and 2.5 Hz), 8.68 (1H, s), 8.58 (1H, d, J 5 9.0 Hz), 8.39 (2H, d, J 5
7.3 Hz), 8.26 (1H, d, J 5 7.2 Hz), 7.61–7.47 (5H, m), 5.04 (1H, dd,
J 5 16.6 and 9.1 Hz), 4.78 (1H, dd, J 5 7.2 and 4.4 Hz), 4.61 (1H, dd,
J 5 9.0 and 4.6 Hz), 4.22 (1H, d, J 5 16.6 Hz), 2.18–2.07 (2H, m), 1.73–
1.64 (1H, m), 1.18–1.09 (1H, m) and 0.98–0.76 (12H, m) ppm; dC
(125 MHz, DMSO-d6) 171.3, 170.3, 163.5, 160.6, 158.0, 155.9, 155.5,
154.6, 151.3, 141.5, 140.2, 140.0, 139.8, 136.1, 131.2, 130.6, 130.4, 129.6,
129.1(62), 127.9(62), 127.2, 122.9, 58.2, 57.8, 38.5, 35.6, 32.1, 25.3,
20.3, 17.9, 15.5 and 12.4 ppm; m/z (ESI) found: 719.2043,
C34H32N8O7SNa [(M + Na)+] requires 719.2012.
natural product YM-216391 produced by S. nobilis.
A concise synthesis of the novel anti-tumour cyclopeptide 1
has therefore been achieved which has also established its
stereochemistry.
We thank the EPSRC for a studentship (to JD) and
Dr Y. Takebayashi (Yamanouchi Pharmaceutical Co. Ltd.,
Ibaraki, Japan) for helpful correspondence and for supplying
relevant NMR spectroscopic data on natural YM-216391. We also
thank David Evans for his contribution to the early part of this
project.
Jon Deeley and Gerald Pattenden*
School of Chemistry, The University of Nottingham, University Park,
Nottingham, UK NG7 2RD. E-mail: gp@nottingham.ac.uk;
Fax: +44 (0)115 951 3535; Tel: +44 (0)115 951 3530
Notes and references
1 K. Hayata, Y. Takebayashi, K. Nagai and M. Hiramoto, Jpn. Kokai
Tokkyo Koho, JP11180997-A, 1999.
2 K. Shin-ya, K. Wierzba, K. Matsuo, T. Ohtani, Y. Yamada,
K. Furihata, Y. Hayakawa and H. Seto, J. Am. Chem. Soc., 2001,
123, 1262–1263; M.-Y. Kim, H. Vankayalapati, K. Shin-ya, K. Wierzba
and L. H. Hurley, J. Am. Chem. Soc., 2002, 124, 2098–2099.
3 A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno and D. R. Williams, Org.
Lett., 2000, 2, 1165–1168; G. Pattenden and T. Thompson, Tetrahedron
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