An approach to the bis-oxazole macrocycle of diazonamides

Article abstract of DOI:10.1021/ol102678j

A convergent approach to a macrocyclic compound embodying the complete "eastern" quadrant of diazonamides is described. The opening sequence in this work relies on an oxazole-forming reaction devised earlier in this group, while a late step involves a Rob

Full text of DOI:10.1021/ol102678j

ORGANIC
LETTERS
2011
Vol. 13, No. 3
390-393
An Approach to the Bis-oxazole
Macrocycle of Diazonamides
Jianmin Zhang and Marco A. Ciufolini*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
Received November 4, 2010
ABSTRACT
A convergent approach to a macrocyclic compound embodying the complete “eastern” quadrant of diazonamides is described. The opening
sequence in this work relies on an oxazole-forming reaction devised earlier in this group, while a late step involves a Robinson-Gabriel
cyclization of an amidoketone to form a second oxazole.
Few natural products have captured so much attention in the
synthetic arena as the diazonamides, 1 (Scheme 1).1 Indeed,
Scheme 1. Structures of Diazonamides A-E
intense activity aiming to conquer their delightfully intricate
structure, initially engendered by the discovery of the first
members of the family,1 continues unabated to this day.2
To wit, since the successful conclusion of the initial synthetic
campaign3 and relative background work,4 two formal
syntheses of 1a5 have appeared in the literature, as have about
half6 of the numerous synthetic studies published to date.7
Noteworthy biological properties8 add a significant dimension
to such chemical pursuits, which, understandably, have
largely focused on the creation of the problematic stereogenic
(1) Isolation of diazonamides A and B and original structural proposal:
Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem.
Soc. 1991, 113, 2303. Isolation of diazonamides C-E: Fernandez, R.;
Martin, M. J.; Rodriguez-Acebes, R.; Reyes, F.; Francesch, A.; Cuevas, C.
Tetrahedron Lett. 2008, 49, 2283.
(2) Reviews: (a) Ritter, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2002,
41, 2489. (b) Lachia, M.; Moody, C. J. Nat. Prod. Rep. 2008, 25, 227. See
also: (c) Nicolaou, K. C.; Chen, J. S. Pure Appl. Chem. 2008, 80, 727. (d)
Delle Monache, G.; Misiti, D.; Zappia, G. Critical surVeys coVering the
year 2002: total synthesis of natural products. In: Seminars in Organic
Synthesis, 28th Summer School “A. Corbella”, Gargnano, Italy, June
16-20, 2003; Marcantoni, E.; Renzi, G.; Eds.; Societa di Chimica Italiana:
Rome, Italy, 2003; pp 329-352.
quaternary center at the core of the molecules. Yet, the
assembly of the bis-oxazole-containing macrocycle that
constitutes the “eastern” portion of diazonamides also raises
interesting chemical issues.7 In that connection, a recent
report from the Moody group9 describes the remarkable
10.1021/ol102678j  2011 American Chemical Society
Published on Web 12/21/2010

biomimetic conversion of 2-3 into 4-5, respectively, under
oxidative conditions (Scheme 2). Such a development
Scheme 2. Moody Biomimetic Oxazole Formation
(3) Synthesis of putative diazonamide and structural revision: (a) Li, J.;
Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4765.
(b) Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.; Harran, P. G. Angew.
Chem., Int. Ed. 2001, 40, 4770. Synthesis of actual diazonamide and
structural confirmation: (c) Nicolaou, K. C.; Bella, M.; Chen, D. Y.-K.;
Huang, X.; Ling, T.; Snyder, S. A. Angew. Chem., Int. Ed. 2002, 41, 3495.
(d) Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.; Huang,
X.; Chen, D. Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003, 42, 1753.
(e) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.; Rassias, G.; Snyder,
S. A.; Huang, X.; Chen, D. Y.-K.; Brenzovich, W. E.; Giuseppone, N.;
Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004, 126, 12897. (f)
Nicolaou, K. C.; Chen, D. Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder,
S. A. J. Am. Chem. Soc. 2004, 126, 12888. (g) Nicolaou, K. C.; Snyder,
S. A.; Giuseppone, N.; Huang, X.; Bella, M.; Reddy, M. V.; Rao, P. B.;
Koumbis, A. E.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004,
126, 10174. (h) Nicolaou, K. C.; Snyder, S. A.; Huang, X.; Simonsen, K. B.;
Koumbis, A. E.; Bigot, A. J. Am. Chem. Soc. 2004, 126, 10162. (i) Burgett,
A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew. Chem., Int. Ed. 2003, 42,
4961.
(4) (a) Jeong, S.; Chen, X.; Harran, P. G. J. Org. Chem. 1998, 63, 8640.
(b) Li, J.; Chen, X.; Burgett, A. W. G.; Harran, P. G. Angew. Chem., Int.
Ed. 2001, 40, 2682. (c) Nicolaou, K. C.; Snyder, S. A.; Simonsen, K. B.;
Koumbis, A. E. Angew. Chem., Int. Ed. 2000, 39, 3473. (d) Nicolaou, K. C.;
Huang, X.; Giuseppone, N.; Rao, P. B.; Bella, M.; Reddy, M. V.; Snyder,
S. A. Angew. Chem., Int. Ed. 2001, 40, 4705.
(5) (a) Cheung, C.-M.; Goldberg, F. W.; Magnus, P.; Russell, C. J.;
Turnbull, R.; Lynch, V. J. Am. Chem. Soc. 2007, 129, 12320. (b) Mai,
C.-K.; Sammons, M. F.; Sammakia, T. Angew. Chem., Int. Ed. 2010, 49,
2397.
prompts us to disclose results of our own efforts in this area.
As outlined in Scheme 3, we have been interested in an
(6) Synthetic studies post-2002: (a) Lin, J.; Gerstenberger, B. S.;
Stessman, N. Y. T.; Konopelski, J. P. Org. Lett. 2008, 10, 3969. (b) Magnus,
P.; Venable, J. D.; Shen, L.; Lynch, V. Tetrahedron Lett. 2005, 46, 707.
(c) Goldberg, F. W.; Magnus, P.; Turnbull, R. Org. Lett. 2005, 7, 4531. (d)
Magnus, P.; Turnbull, R. Tetrahedron Lett. 2006, 47, 6461. (e) Palmer,
F. N.; Lach, F.; Poriel, C.; Pepper, A. G.; Bagley, M. C.; Slawin, A. M. Z.;
Moody, C. J. Org. Biomol. Chem. 2005, 3, 3805. (f) Bagley, M. C.; Hind,
S. L.; Moody, C. J. Tetrahedron Lett. 2005, 46, 8621. (g) Davies, J. R.;
Kane, P. D.; Moody, C. J. J. Org. Chem. 2005, 70, 7305. (h) Sperry, J.;
Moody, C. J. Chem. Commun. 2006, 2397. (i) Poriel, C.; Lachia, M.; Wilson,
C.; Davies, J. R.; Moody, C. J. J. Org. Chem. 2007, 72, 2978. (j) Booker,
J. E. M.; Boto, A.; Churchill, G. H.; Green, C. P.; Ling, M.; Meek, G.;
Prabhakaran, J.; Sinclair, D.; Blake, A. J.; Pattenden, G. Org. Biomol. Chem.
2006, 4, 4193. (k) Zajac, M. A.; Vedejs, E. Org. Lett. 2004, 6, 237. (l)
Sawada, T.; Fuerst, D. E.; Wood, J. L. Tetrahedron Lett. 2003, 44, 4919.
See also: (m) Yuen, A. K. L.; Hutton, C. A. Nat. Prod. Commun. 2006, 1,
907.
Scheme 3. Approach to Diazonamides
(7) Synthetic studies up to 2002: (a) Feldman, K. S.; Eastman, K. J.;
Lessene, G. Org. Lett. 2002, 4, 3525. (b) Konopelski, J. P.; Hottenroth,
J. M.; Oltra, H. M.; Veliz, E. A.; Yang, Z. C. Synlett 1996, 609. (c) Hang,
H. C.; Drotleff, E.; Elliott, G. I.; Ritsema, T. A.; Konopelski, J. P. Synthesis
1999, 398. (d) Radspieler, A.; Liebscher, J. Synthesis 2001, 745. (e) Schley,
D.; Radspieler, A.; Christoph, G.; Liebscher, J. Eur. J. Org. Chem. 2002,
369. (f) Magnus, P.; Kreisberg, J. D. Tetrahedron Lett. 1999, 40, 451. (g)
Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41, 831. (h) Kreisberg,
J. D.; Magnus, P.; McIver, E. G. Tetrahedron Lett. 2001, 42, 627. (i) Chan,
F.; Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41, 835. (j) Magnus,
P.; Lescop, C. Tetrahedron Lett. 2001, 42, 7193. (k) Moody, C. J.; Doyle,
K. J.; Elliott, M. C.; Mowlem, T. J. Pure Appl. Chem. 1994, 66, 2107. (l)
Moody, C. J.; Doyle, K. J.; Elliott, M. C.; Mowlem, T. J. J. Chem. Soc.,
Perkin Trans. 1 1997, 16, 2413. (m) Lach, F.; Moody, C. J. Tetrahedron
Lett. 2000, 41, 6893. (n) Bagley, M. C.; Hind, S. L.; Moody, C. J.
Tetrahedron Lett. 2000, 41, 6897. (o) Bagley, M. C.; Moody, C. J.; Pepper,
A. G. Tetrahedron Lett. 2000, 41, 6901. (p) Boto, A.; Ling, M.; Meek, G.;
Pattenden, G. Tetrahedron Lett. 1998, 39, 8167. (q) Vedejs, E.; Wang, J.
Org. Lett. 2000, 2, 1031. (r) Vedejs, E.; Barda, D. A. Org. Lett. 2000, 2,
1033. (s) Vedejs, E.; Zajac, M. A. Org. Lett. 2001, 3, 2451. (t) Wipf, P.;
Methot, J.-L. Org. Lett. 2001, 3, 1261. (u) Fuerst, D. E.; Stoltz, B. M.;
Wood, J. L. Org. Lett. 2000, 2, 3521. See also: (v) Motallebi, S.; Mueller,
P. HelV. Chim. Acta 1993, 76, 2803.
approach that would advance synthetic intermediate 6 (Z )
appropriate electrophilic functionality) to the natural products.
In turn, compound 6 would be obtained from 8 via
Robinson-Gabriel oxazole formation and further elaboration
of the resultant macrolactam 7. The synthesis of 8 could
proceed through the union of oxazoles 9, which should be
available through an oxazole-forming reaction developed
earlier in this group,10 and 4-aryltryptamine 10. Herein, we
detail procedures for the implementation of such a plan.
The condensation of valine-derived chloroglycinate 1111
with the dimethylaluminum acetylide prepared from
(8) See ref 1 as well as: (a) Cruz-Monserrate, Z.; Vervoort, H. C.; Bai,
R.; Newman, D. J.; Howell, S. B.; Los, G.; Mullaney, J. T.; Williams, M. D.;
Pettit, G. R.; Fenical, W.; Hamel, E. Mol. Pharmacol. 2003, 63, 1273. (b)
Cruz-Monserrate, Z.; Mullaney, J. T.; Harran, P. G.; Pettit, G. R.; Hamel,
E. Eur. J. Biochem. 2003, 270, 3822. (c) Singh, R.; Sharma, M.; Joshi, P.;
Rawat, D. S. Anti-Cancer Agents Med. Chem. 2008, 8, 603. (d) Wang, G.;
Shang, L.; Burgett, A. W. G.; Harran, P. G.; Wang, X. Proc. Natl. Acad.
Sci. U.S.A. 2007, 104, 2068. (e) Williams, N. S.; Burgett, A. W. G.; Atkins,
A. S.; Wang, X.; Harran, P. G.; McKnight, S. L. Proc. Natl. Acad. Sci.
U.S.A. 2007, 104, 2074.
(9) Sperry, J.; Moody, C. J. Tetrahedron 2010, 66, 6483. See also ref
6g.
Org. Lett., Vol. 13, No. 3, 2011
391

benzyl propargyl ether (Scheme 4; Pht ) phthalimido)
afforded enantiopure oxazole 12. Without extensive
DDQ, followed by IBX oxidation of the intermediate
carbinol 20.6g Both 19 and 21 underwent simultaneous
cleavage of the CBZ and ethyl ester groups upon exposure
to BBr3 to afford the extremely polar amino acids 22 and
23, respectively (Scheme 6). These were not thoroughly
Scheme 4. Oxazole Formation from R-Chloroglycinates
Scheme 6. Preparation of Macrocyclic Compounds 25 and 26
purification, this material was debenzylated (BCl3) to
furnish alcohol 13, a substance that proved to be quite
sturdy, being best advanced to acid 14 by Jones oxidation.
Acid chloride 15 emerged uneventfully upon treatment
of 10 with SOCl2.
Parallel work yielded 4-arylindole 18, prepared by Pd-
mediated coupling of commercial boronic ester 16 with
the known 176g (Scheme 5). Substance 18 is axially chiral,
Scheme 5. Coupling of 15 and 18 and Oxidation of Product 19
characterized. Instead, they were immediately cyclized
(HATU)13 to afford macrolactams 25 and 26 (68% and
77% overall yield, respectively). It is unclear at this time
whether this transformation occurred by direct nucleophilic
attack of the amino group onto the HATU-activated
carboxyl group or through the intervention of an azlactone-
type intermediate such as 24. Regardless, it is worthy of
note that, contrary to the case of 19, the action of aqueous
DDQ upon 25 failed to induce hydroxylation in an efficient
manner, preventing a possible conversion into 26. In this
respect, the behavior of 25 differs from that of a related
system described by Moody,6g,14 which underwent the
oxidation in question in 84% yield, underscoring the fact
that the reactivity of such macrocycles is quite sensitive to
structural details.
Finally, exposure of 26 to the action of TsOH in refluxing
toluene triggered formation of bis-oxazole 27, a 1:1 mixture
(10) (a) Coqueron, P. Y.; Didier, C.; Ciufolini, M. A. Angew. Chem.,
Int. Ed. 2003, 42, 1411. Recent developments: (b) Zhang, J.; Coqueron,
P. Y.; Vors, J. P.; Ciufolini, M. A. Org. Lett. 2010, 12, 3942. (c) Zhang, J.;
Ciufolini, M. A. Org. Lett. 2009, 11, 2389. (d) Zhang, J.; Polishchuk, E. A.;
Chen, J.; Ciufolini, M. A. J. Org. Chem. 2009, 74, 9140. (e) Chau, J.; Zhang,
J.; Ciufolini, M. A. Tetrahedon Lett. 2009, 50, 6163. Review: (f) Zhang,
J.; Coqueron, P. Y.; Ciufolini, M. A. Heterocycles 2010, 77, in press [DOI:
10.3987/REV-10-SR(E)3].
but for the purpose of the present study it was employed
as the racemate.12 The condensation of 15 with 18 was
difficult, presumably on account of the hindered nature
of the amino group, and it proceeded to furnish 19 in a
moderate 39% yield. This material, resulting through the
union of enantiopure 15 with racemic 18, was obtained
as a 1:1 mixture of atrop-diastereomers, as were all
subsequent synthetic intermediates derived from it. Con-
version of 19 into 21, as required for the ultimate
formation of the second oxazole ring in a Robinson-Gabriel
mode, was achieved in 73% yield by hydroxylation with
(11) Ref 10 as well as: Zhang, J. Tetrahedron Lett. 2010, 51, 4699
.
(12) No literature record of compound 18 appears to exist, but the
corresponding 4-(3-aminophenyl) indole has been described in a recent
patent application: Wells, J.; Renslo, A. R.; Wolan, D.; Zorn, J. PCT Int.
Appl. ( 2009),WO 2009089508.
(13) Carpino, L. J. Am. Chem. Soc. 1993, 115, 4397
.
(14) The Moody substrate differs from 25 in that the oxazole ring and
the benzene nucleus are bridged by a plain methylene group (i.e., the
CO-NH linkage is missing), which furthermore connects to the meta
position of the phenyl group.
392
Org. Lett., Vol. 13, No. 3, 2011

of atrop-diastereomers, in 34% yield after purification
(Scheme 7). This compound embodies a specific example
of generic intermediate 7. Its successful formation in the
fashion just described validates the surmise of Scheme 3, it
complements the Moody approach, and it delineates a
heretofore unexplored route to the “eastern” segment of
diazonamides. Research aiming to advance 27 to a totally
synthetic diazonamide continues, and results in this area will
be described in due course.
Scheme 7
.
Robinson-Gabriel Route to Macrocyclic Bis-oxazole
27
Acknowledgment. We thank the University of British
Columbia, the Canada Research Chair Program, CFI, BCK-
DF, NSERC, CIHR, and Merck Frosst Canada for financial
support.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds, plus
NMR (1H and 13C) spectra of several products. This material
is available free of charge via the Internet at http://pubs.acs.org.
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