Synthetic studies toward diazonamide A. A novel approach for polyoxazole synthesis

Article abstract of DOI:10.1021/ol0157196

(equation presented) The indole-bisoxazole fragment of diazonamide A was prepared by a Chan-type rearrangement of a tertiary amide. This approach represents a remarkably direct strategy for polyoxazole synthesis.

Full text of DOI:10.1021/ol0157196

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1261-1264
Synthetic Studies toward Diazonamide A.
A Novel Approach for Polyoxazole
Synthesis
Peter Wipf* and Joey-Lee Methot
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf+@pitt.edu
Received February 16, 2001
ABSTRACT
The indole−bisoxazole fragment of diazonamide A was prepared by a Chan-type rearrangement of a tertiary amide. This approach represents
a remarkably direct strategy for polyoxazole synthesis.
The architectural complexity of the cytotoxic marine me-
tabolite diazonamide A (1) presents a daunting challenge to
the synthetic chemist. Isolated in 1991 from the colonial
ascidian Diazona chinensis, this halogenated cyclic peptide
demonstrated impressive in vitro activity against HCT-116
human colon carcinoma and B-16 murine melanoma cancer
cell lines (IC50 < 15 ng/mL).1 Unfortunately, a shortage of
the natural material is preventing further biological study.
The unique structure of diazonamide A, a complex
macrocyclic arrangement of heteroaromatic rings linked
through biaryl linkages and a deeply embedded quaternary
center, was established by an X-ray crystal structure.1 Several
academic groups have reported progress toward the total
synthesis of this formidable target.2
Previously, we reported a sequence leading to benzofura-
none-indolyloxazole fragment 4 featuring a Heck annulation
to set the quaternary center (Figure 1).2e We envisioned that
cyclization of a hydroxy acid or amino acid to form a lactone
or lactam, followed by Chan ring contraction, might be an
efficient strategy for closure of the 12-membered B-ring (3
f 2) and for positioning the functionality necessary for
annulation of the a2-oxazole.
Although quite attractive from a retrosynthetic perspective
the original Chan rearrangement3 of R-acyloxyacetates
(2) (a) Moody, C. J.; Doyle, K. J.; Elliott, M. C.; Mowlem, T. J. Pure
Appl. Chem. 1994, 66, 2107-2110. (b) Konopelski, J. P.; Hottenroth, J.
M.; Oltra, H. M.; Veliz, E. A.; Yang, Z.-C. Synlett 1996, 609-611. (c)
Moody, C. J.; Doyle, K. J.; Elliott, M. C.; Mowlem, T. J. J. Chem. Soc.,
Perkin Trans. 1 1997, 2413-2419. (d) Jamison, T. F. Ph.D. Dissertation,
Harvard University, Cambridge, MA, 1997. (e) Wipf, P.; Yokokawa, F.
Tetrahedron Lett. 1998, 39, 2223-2226. (f) Boto, A.; Ling, M.; Meek, G.;
Pattenden, G. Tetrahedron Lett. 1998, 39, 8167-8170. (g) Jeong, S.; Chen,
X.; Harran, P. G.; J. Org. Chem. 1998, 63, 8640-8641. (h) Hang, H. C.;
Drotleff, E.; Elliott, G. I.; Ritsema, T. A.; Konopelski, J. P. Synthesis 1999,
3, 398-400. (i) Magnus, P.; Kreisberg, J. D. Tetrahedron Lett. 1999, 40,
451-454. (j) Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41, 831-
834. (k) Chan, F.; Magnus, P.; McIver, E. Tetrahedron Lett. 2000, 41, 835-
838. (l) Chen, X.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2000,
39, 937-940. (m) Vedejs, E.; Wang, J. Org. Lett. 2000, 2, 1031-1032.
(n) Vedejs, E.; Barda, D. A. Org. Lett. 2000, 2, 1033-1035. (o) Lach, F.;
Moody, C. J. Tetrahedron Lett. 2000, 41, 6893-6896. (p) Bagley, M. C.;
Hind, S. L.; Moody, C. J. Tetrahedron Lett. 2000, 41, 6897-6900. (q)
Bagley, M. C.; Moody, C. J.; Pepper, A. G. Tetrahedron Lett. 2000, 41,
6901-6904. (r) Nicolaou, K. C.; Snyder, S. A.; Simonsen, K. B.; Koumbis,
A. E. Angew. Chem., Int. Ed. 2000, 39, 3473-3478. (s) Fuerst, D. E.; Stoltz,
B. M.; Wood, J. L. Org. Lett. 2000, 2, 3521-3523.
(1) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem.
Soc. 1991, 113, 2303-2304.
(3) Lee, S. D.; Chan, T. H.; Kwon, K. S. Tetrahedron Lett. 1984, 25,
3399-3402.
10.1021/ol0157196 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/04/2001

Figure 1. Retrosynthetic analysis of diazonamide A.
(I) into 2-hydroxy-3-ketoesters (II) has received only moder-
ate attention in natural product synthesis.4
lecular Claisen product 6, with no trace of the desired Chan
product 7.
We reasoned that a more rapid benzylic anion formation
might prevent the Claisen side reaction. Thus a series of
R-silyl benzyl pivaloates (8) were prepared5 and subjected
to anhydrous fluoride sources such as CsF and tetrabutyl-
ammonium triphenyldifluorosilicate (TBAT).6 Even under
forcing conditions (e.g., heat in the presence of molecular
sieves), only protodesilylation was observed. In contrast,
addition of benzaldehyde led to monoacylated hydrobenzoin
9.7
Since we were unable to achieve the synthesis of hydroxy
ketones of type 7, we turned our attention to a report by
Hamada and co-workers on N f C acyl migrations of acyclic
imides.8 Upon warming of imide 10 to -10 °C, we obtained
indeed a 69% yield of the desired R-amino ketone 11. One
explanation for the success of this model is the relative
population of s-cis and s-trans conformations of the ester
and tertiary amide, since only the s-cis conformation is likely
to undergo the rearrangement.9
Since it was not clear if the acidity of a benzylic methylene
group was sufficient to allow for a Chan reaction, we initiated
model studies with benzyl pivaloate (Scheme 1). However,
attempts to rearrange 5 with LDA led only to the intermo-
Scheme 1. Preliminary Model Studies
As an extension of this strategy, we tested the feasibility
of oxazole-substituted imides to undergo selective Chan
(4) (a) White, J. D.; Vedananda, T. R.; Kang, M.; Choudhry, S. C. J.
Am. Chem. Soc. 1986, 108, 8105-8107. (b) White, J. D.; Avery, M. A.;
Choudhry, S. C.; Dhingra, O. P.; Gray, B. D.; Kang, M.; Kuo, S.; Whittle,
A. J. J. Am. Chem. Soc. 1989, 111, 790-792. (c) Holton, R. A.; Somoza,
C.; Kim, H.; Liang, F.; Biediger, R. J.; Boatman, D.; Shindo, M.; Smith,
C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang,
P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116,
1597-1598. (d) White, J. D.; Jeffrey, S. C. J. Org. Chem. 1996, 61, 2600-
2601.
(5) The dimethylphenylsilyl derivative was prepared by addition of
PhMe2SiLi to benzaldehyde followed by acylation, while the TMS and TBS
derivatives were prepared by a retro-Brook rearrangement (Linderman, R.
J.; Ghannam, A. J. Am. Chem. Soc. 1990, 112, 2392-2398) on the
R-tributylstannyl silyl-protected benzyl alcohol followed by acylation.
(6) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901-6905.
(7) A 1:1 mixture of stereoisomers was obtained.
(8) Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39, 5537-
5540.
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Org. Lett., Vol. 3, No. 9, 2001

Scheme 2. Polyoxazoles via Sequential Chan Reactions
Scheme 3. Synthesis of the Indolyl Bisoxazole Fragment of
Diazonamide A
synthesis. Polyoxazoles and other polyazoles are noteworthy
structural features of many bioactive natural products.10
rearrangements (Scheme 2). Imide 13 was prepared in four
steps from 2-aminoacetophenone hydrochloride. The Chan
rearrangement on this substrate was even more facile, and
C(5)-deprotonation or arene metalation did not interfere,
giving the desired amino ketone 14 in 89% yield after 30
min at -78 °C.
A more representative model 20 for our planned total
synthesis of diazonamide A contains the indole nucleus and
a more crowded quaternary center (Scheme 3).
Amino ketone 18 was prepared in two steps from indole
via the acyl cyanide as described by Horne et al.11 Coupling
to N-Cbz-glycine, cyclodehydration,12 and protection of the
indole provided indolyloxazole 19. Hydrogenolysis and
coupling to Ph2(Me)CCO2H followed by amide protection
yielded imide 20. Ph2(Me)CCO2H was selected as the acyl
component because it provides an adequate substitute for
the a1/b2 ring system at C(10) of diazonamide A. The key
LDA-mediated Chan rearrangement proceeded smoothly
on this model, giving amino ketone 21 in 78% yield.
For the completion of the indole-bisoxazole fragment of
the natural product, the Boc group of 21 was cleaved
and the resulting amine coupled to N-Cbz-valine. Acid-
mediated cyclodehydration then introduced bisoxazole
22 in >90% enantiomeric purity.13 The straightforward
conversion of 21 to 22 is a further demonstration of how
tightly the imide Chan reaction integrates with oxazole
synthesis.
The sequential Chan reaction represents a general method
for polyoxazole synthesis. Thus, HCl-mediated cleavage of
the Boc group followed by coupling to N-benzoylglycine
and TsOH-mediated cyclodehydration afforded bisoxazole
15. Boc-protection and another Chan rearrangement (LDA,
-78 °C, 85% yield) furnished aryl ketone 16. Finally,
elaboration to trisoxazole 17 was achieved by coupling of
the unmasked amine to N-Cbz-glycine with isobutyl chlo-
roformate (IBCF) and cyclodehydration. The four-step
sequence from 15 to 17 represents one cycle for polyoxazole
(9) Calculations (6-31G*) suggest little ground-state energy preference
for the s-trans conformation over the s-cis (1.4 kcal/mol) for the imide. In
the case of the ester, this preference is considerable (>16 kcal/mol).
(10) Wipf, P.; Venkatraman, S. Synlett 1997, 1-10.
(11) Miyaka, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000, 2,
2121-2123.
(12) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604-3606.
(13) Determined by analysis of the Mosher amide derivatives of 22 with
both (R)- and (S)-MTPA. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org.
Chem. 1969, 34, 2543-2549.
Org. Lett., Vol. 3, No. 9, 2001
1263

In conclusion, a new modification of the Chan rearrange-
ment has been developed that serves as the basis of a versatile
and direct strategy for iterative polyoxazole synthesis. As
R-amino ketone 21 demonstrates, products of this Chan
reaction are potentially well suited for annulation of oxazole
a2 onto the B-macrocycle of the complex natural product
diazonamide A. Further progress along this retrosynthetic
plan will be reported in due course.
Acknowledgment. We are grateful to the National
Institutes of Health (GM 55433) for support of this research.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 12-17 and 19-
22. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0157196
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Org. Lett., Vol. 3, No. 9, 2001