Rapid and convergent synthesis of a 2,4'-linked tri-oxazole in an approach to poly-oxazoles

Article abstract of DOI:10.3987/COM-12-S(N)118

A rapid and convergent synthesis of a 2,4'-linked tri-oxazole using a Negishi coupling is described.

Full text of DOI:10.3987/COM-12-S(N)118

HETEROCYCLES, Vol. 86, No. 2, 2012
1003
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1003 - 1008. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 3rd September, 2012, Accepted, 22nd October, 2012, Published online, 12th November, 2012
DOI: 10.3987/COM-12-S(N)118
RAPID AND CONVERGENT SYNTHESIS OF
A
2,4’-LINKED
TRI-OXAZOLE IN AN APPROACH TO POLY-OXAZOLES
Daniel D. Caspi, Haiming Zhang, Scott C. Virgil, Fabian M. Piller, and Brian
M. Stoltz*
The Warren and Katharine Schlinger Laboratory of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125,
United States
stoltz@caltech.edu
Abstract – A rapid and convergent synthesis of a 2,4’-linked tri-oxazole using a
Negishi coupling is described.
Due to the biological importance of polyoxazole-containing compounds, a multitude of synthetic
approaches have been described.1 While preparations of mono- and di-substituted oxazoles are common,
reports describing the synthesis of longer oxazole chains are much more scarce.2,3 We became interested
in efficient routes to 2,4’-polyoxazoles during studies on the total synthesis of telomestatin (1, Scheme 1),
a potent telomerase inhibitor.4-7 Herein, we present a rapid and convergent synthesis of a 2,4’-linked
tri-oxazole using a Negishi coupling.
Our retrosynthetic analysis for telomestatin (1) is featured Scheme 1. On the basis of the reported
telomestatin (1) syntheses,5 we envisioned a late-stage installation of the sulfur moiety and the thiazoline
ring. Additionally, in order to maximize synthetic efficiency, we sought to complete the final aryl–aryl
linkage of 2 and induce macrocyclization using a palladium-catalyzed cross-coupling.8,9 This maneuver
would also allow for a high degree of convergency by dividing the molecule into two roughly equal
halves. Disconnection across the amide bond in 2 then reveals tri-oxazole fragment 3 and tetrakis-oxazole
amino alcohol 4.
Dedicated to Professor Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
O
S
N
N
N
O
O
N
N
N
N
O
O
N
O
O
telomestatin (1)
Pd-Catalyzed
Macrocyclization
&
Thiazoline Formation
HO
OH
O
O
O
O
H2N
OEt
N
H
N
N
O
O
N
O
O
N
N
N
N
N
O
N
O
O
O
N
O
O
N
N
N
N
O
O
TfO
I
TfO
3
2
4
Scheme 1
Our synthesis of the left-hand tri-oxazole portion (3) of telomestatin (1) began with the preparation of
known oxazole ester 7. Exposure of ethyl isocyanoacetate (5) to mixed anhydride 610 and DBU led to a
high yield of oxazole ester 7,11 which was smoothly converted to amide 8 by the action of aqueous
ammonia in methanol (Scheme 2). Conversion to bis-oxazole triflate 12 was achieved by means of a
three-step sequence, which commenced by heating amide 8 in the presence of oxalyl chloride to give rise
to acyl isocyanate 9.

HETEROCYCLES, Vol. 86, No. 2, 2012
1005
O
O
O
H
O
O
O
NH4OH
OEt
(COCl)2
6
NH2
OEt
DBU, THF
0 °C ! 23 °C
MeOH, 23 °C
O
DCE, 85 °C
CN
O
N
N
(90% yield)
Ethyl
Isocyanoacetate (5)
(94% yield)
7
8
O
O
+
N2
OEt
OEt
O
OTf
O
O
O
N
N
O
O
O
O
O
Tf2O, Et3N
•
CH2N2
Et2O
N
N
N
13
N
ClZn
THF, –78 °C
N
10 mol % Pd(PPh3)4
THF, 65 °C
O
N
N
N
N
(52% yield,
3 steps)
O
O
O
O
N
12
(89% yield)
9
10
11
O
3
Scheme 2
Subjection of acyl isocyanate 9 to anhydrous, alcohol-free diazomethane dried over sodium metal12 led to
in situ production of 10, which rapidly cyclized with loss of nitrogen to form oxazolone 11.13 Treatment
of this intermediate with Tf2O and amine base produced bis-oxazole triflate 12 in 52% yield over 3
steps.14 Further confirmation of the structural identity was achieved by single crystal X-ray diffraction
upon conversion to the iodo derivative (12 ! 14, Scheme 3).15
F
F
O
F
OTf
S
OTf
O
O
O
O
N
I2
N
N
O
n-BuLi, THF
N
–78 °C
O
N
O
(86% yield)
N
I
O
12
14
I
14
Scheme 3
A wide range of cross-couplings of appropriate mono- and bis-oxazole subunits were investigated to
prepare the desired tri-oxazole fragment (3), including Stille, Suzuki, and Negishi protocols.16,17
Ultimately, the Negishi approach proved to be the most robust to accomplish this union. The necessary
zinc reagent (13) for this reaction could be prepared from 7 via a deprotonation/quenching event with
LiHMDS and ZnCl2, furnishing tri-oxazole 3 after successful aryl fusion with bis-oxazole 12.18 This
approach was also used in a similar fashion to prepare a tetrakis-oxazole.19

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HETEROCYCLES, Vol. 86, No. 2, 2012
In conclusion, we have presented an efficient and convergent synthesis of a tri-oxazole fragment. Existing
studies to utilize this methodology toward a total synthesis of telomestatin are ongoing in our laboratory.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the NIH-NIGMS (R01 GM65961-01), Eli Lilly (predoctoral
fellowship to D.D.C.), AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, Pfizer, Merck, Amgen,
Research Corporation, Roche, and GlaxoSmithKline for generous funding. We also thank Tim Dong and
J. T. Mohr for experimental assistance.
REFERENCES (AND NOTES)
1. For a review on oxazole-containing natural products, see: V. S. C. Yeh, Tetrahedron, 2004, 60,
11995.
2. For a review on directly linked polyazoles, see: (a) E. Riego, D. Hernández, F. Albericio, and M.
Álvarez, Synthesis, 2005, 1907; (b) C. D. Turner and H. S. Liang, Curr. Org. Chem., 2011, 15, 2846.
3. For excellent and comprehensive discussions on oxazole methodologies, see: (a) E. F. Flegeau,
“Palladium Cross-Couplings of Oxazoles”. Ph.D. dissertation, Edinburgh University, 2008; (b) E.
Charalambidou, “Synthesis of oxazole ring systems for use as inhibitors of telomerase function”.
Masters thesis, University College London, 2008.
4. 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.
5. For the total synthesis of telomestatin, see: (a) S. Yamada, K. Shigeno, K. Kitagawa, S. Okajima,
and T. Asao (Taiho Pharmaceutical Co. Ltd., Sosei Co. Ltd.), WO2002048153 (Chem. Abstr. 2002,
137, 47050); (b) T. Doi, M. Yoshida, K. Shin-ya, and T. Takahashi, Org. Lett., 2006, 8, 4165; (c)
For the synthesis of (S)-telomestatin, see: T. Doi, K. Shibata, M. Yoshida, M. Takagi, M. Tera, K.
Nagasawa, K. Shin-ya, and T. Takahashi, Org. Biomol. Chem., 2011, 9, 387; (d) For a formal total
synthesis, see: J. Linder, T. P. Garner, H. E. L. Williams, M. S. Searle, and C. J. Moody, J. Am.
Chem. Soc., 2011, 133, 1044.
6. For approaches toward telomestatin, see: (a) N. Endoh, K. Tsuboi, R. Kim, Y. Yonezawa, and C.
Shin, Heterocycles, 2003, 60, 1567; (b) S. K. Chattopadhyay and S. Biswas, Tetrahedron Lett., 2006,
47, 7897; (c) S. K. Chattopadhyay, S. Biswas, and B. K. Pal, Synthesis, 2006, 1289; (d) C. M.
Marson and M. Saadi, Org. Biomol. Chem., 2006, 4, 3892.
7. D. D. Caspi, “The Adaptive Nature of Palladium Reactivity in Synthesis”, Ph.D. dissertation,
California Institute of Technology, 2008.
8. For examples of palladium-catalyzed biaryl formation for macrocyclization, see: (a) H. K. Patel, J. D.

HETEROCYCLES, Vol. 86, No. 2, 2012
1007
Kilburn, G. J. Langley, P. D. Edwards, T. Mitchell, and R. Southgate, Tetrahedron Lett., 1994, 35,
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Chem., 2005, 1949.
9. Heteroaryl–heteroaryl cross-couplings, especially those containing nitrogen heterocycles, often
exhibit poor reactivity. For relevant discussions, see: (a) N. Kudo, M. Perseghini, and G. C. Fu,
Angew. Chem. Int. Ed., 2006, 45, 1282 and references therein; (b) K. L. Billingsley, K. W. Anderson,
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Org. Chem., 1996, 61, 6552; (b) W. K. Fife and Z.-d. Zhang, J. Org. Chem., 1986, 51, 3744; (c) C. R.
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T. Izzo, J. Am. Chem. Soc., 1949, 71, 4059; (b) Y. S. Rao and R. Filler, Chem. Commun., 1970,
1622; (c) R. M. Rodehorst and T. H. Koch, J. Am. Chem. Soc., 1975, 97, 7298; (d) T. R. Kelly and F.
Lang, Tetrahedron Lett., 1995, 36, 5319; (e) J. V. Schaus and J. S. Panek, Org. Lett., 2000, 2, 469;
(f) A. B. Smith, III, K. P. Minbiole, and S. Freeze, Synlett, 2001, 1739; (g) A. B. Smith, III, K. P.
Minbiole, P. R. Verhoest, and M. Schelhaas, J. Am. Chem. Soc., 2001, 123, 4834; (h) A. B. Smith,
III, K. P. Minbiole, P. R. Verhoest, and M. Schelhaas, J. Am. Chem. Soc., 2001, 123, 10942; (i) T. R.
Kelly and F. Lang, J. Org. Chem., 1996, 61, 4623; (j) N. F. Langille, L. A. Dakin, and J. S. Panek,
Org. Lett., 2002, 4, 2485; (k) B. M. Trost, K. Dogra, and M. Franzini, J. Am. Chem. Soc., 2004, 126,
1944; (l) A. B. Smith, III, T. M. Razler, G. R. Pettit, and J.-C. Chapuis, Org. Lett., 2005, 7, 4403;
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M. Barrett and J. T. Kohrt, Synlett, 1995, 415.
14. Although no characterization data or experimental details were provided, the synthesis of compound
12 via a related route was reported. See H. Araki, T. Katoh, and M. Inoue, Tetrahedron Lett., 2007,
48, 3713. An alternate route to 12 from 8 is also described in the supporting information (23%
overall yield).
15. See supporting information; iodobis-oxazole triflate 14 is shown with 50% probability ellipsoids
(Note: Only Molecule A is depicted). Crystallographic data have been deposited at the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, and copies can be obtained on request, free of charge, by
quoting the publication citation and the deposition number 282586.
16. For useful reports of oxazole cross-couplings, see reference 3 and references therein.

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HETEROCYCLES, Vol. 86, No. 2, 2012
17. For Negishi cross-couplings of oxazoles, see: (a) N. K. Harn, C. J. Gramer, and B. A. Anderson,
Tetrahedron Lett., 1995, 36, 9453; (b) B. A. Anderson and N. K. Harn, Synthesis, 1996, 583; (c) B.
A. Anderson, L. M. Becke, R. N. Booher, M. E. Flaugh, N. K. Harn, T. J. Kress, D. L. Varie, and J.
P. Wepsiec, J. Org. Chem., 1997, 62, 8634; (d) E. Vedejs and L. M. Luchetta, J. Org. Chem., 1999,
64, 1011; (e) M. R. Reeder, H. E. Gleaves, S. A. Hoover, H. R. Imbordino, and J. Pangborn, Org.
Process Res. Dev., 2003, 7, 696.
18. Although no characterization data or experimental details were provided, the synthesis of 3 was
reported in reference 13. The synthesis of 3 has also been reported by: E. F. Flegeau, M. E. Popkin,
and M. F. Greaney, Org. Lett., 2008, 10, 2717.
19. This approach was also successful in producing small quantities of tetrakis-oxazole ii, which was
prepared from triflate 12 and Negishi reagent i. Negishi reagent i was made in a two-step process:
ethoxycarbonylation of 12, followed by metalation in a similar fashion as 13.
O
O
O
OEt
N
OEt
OTf
O
O
N
N
O
N
i
ClZn
N
O
10 mol % Pd(PPh3)4
THF, 65 °C
O
N
O
N
12
N
O
ii