A tyrosine-derived benzofuranone related to diazonamide A.

Article abstract of DOI:10.1021/ol005547x

[formula: see text] Cyclization of 8 with PPA followed by MCPBA oxidation affords the benzofuranone 10. Treatment with a chiral chloroformate in the presence of DMAP affords the target benzofuranone 13 via an enol ester 12.

Full text of DOI:10.1021/ol005547x

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1031-1032
A Tyrosine-Derived Benzofuranone
Related to Diazonamide A
,†
Edwin Vedejs* and Jiabing Wang
Chemistry Department, UniVersity of Wisconsin, Madison, Wisconsin 53705
edVed@umich.edu
Received January 13, 2000
ABSTRACT
Cyclization of 8 with PPA followed by MCPBA oxidation affords the benzofuranone 10. Treatment with a chiral chloroformate in the presence
of DMAP affords the target benzofuranone 13 via an enol ester 12.
Diazonamide A (1) has attracted attention due to the
unprecedented macrocyclic ring system and preliminary
indications of biological activity.1 In vitro, 1 exhibits IC50
values of less than 15 ng/mL against HCT-116 human colon
carcinoma and B-16 murine melanoma cell lines. Although
the structure and activity have been known since 1991,
further biological studies have been hampered by the limited
availability of natural material.
The choice of 2 as the generic target was based on the
premise that the hemiacetal subunit of diazonamide A is free
to equilibrate between the C-7 and C-17 phenolic hydroxyls.
Either regioisomeric benzofuranone is therefore a suitable
target, assuming selective lactone carbonyl reduction, and 2
was selected because a simple sequence should allow furan
annulation via O-alkylation of a protected tyrosine, followed
by electrophilic ring closure.
Several groups have reported progress with some of the
structural subunits.2 Our own work has been directed toward
assembly of the lower periphery of the molecule.3 Here, we
describe the synthesis of a benzofuranone of the general
structure 2. The accompanying communication reports the
synthesis of the indole subunit of diazonamide A, including
methodology for incorporation of the C-24 oxazolyl and C-18
aryl substituents.4
The chloromethyl ketone 6 was prepared from 3 by the
addition of the known Grignard reagent 45 to acetaldehyde,
followed by Swern oxidation and chlorination. The subse-
quent O-alkylation of the protected tyrosine methyl ester 7
with 6 was somewhat difficult to control, but an acceptable
71% yield of 8 was obtained using anhydrous two-phase
conditions (dichloromethane/K2CO3). Phase transfer condi-
tions in the presence of tetrabutylammonium bromide were
also tested, but the yield of 8 was lower (50%). Cyclization
of 8 to 9 worked well in refluxing benzene with polyphos-
phoric acid as the catalyst (84% yield), and oxidative
conversion to the lactone 10 (81%) occurred upon treatment
with peracetic acid.
† Current address: Department of Chemistry, University of Michigan,
Ann Arbor, MI 48109.
(1) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem.
Soc. 1991, 113, 2303.
(2) (a) Moody, C. J.; Doyle, K J.; Elliott, M. C.; Mowlem, T. J. Pure
Appl. Chem. 1994, 66, 2107. (b) Konopelski, J. P.; Hottenroth, J. M.; Oltra,
H. M.; Veliz, E. A.; Yang, Z.-C. Synlett 1996, 609. (c) Moody, C. J.; Doyle,
K. J.; Elliott, M. C.; Mowlem, T. J. J. Chem. Soc., Perkin Trans. 1 1997,
2413. (d) Boto, A.; Ling, M.; Meek, G.; Pattenden, G. Tetrahedron Lett.
1998, 39, 8167. (e) Wipf, P.; Yokokawa, F. Tetrahedron Lett. 1998, 39,
2223. (f) Hang, H. C.; Drotleff, E.; Elliott, G. I.; Ritsema, T. A.; Konopelski,
J. P. Synthesis 1999, 398. (g) Jeong, S.; Chen, X.; Harran, P. G. J. Org.
Chem. 1999, 63, 8640. (h) Magnus, P.; Kreisberg, J. D. Tetrahedron Lett.
1999, 40, 451. Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41, 831.
Chan, F.; Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41, 835.
(3) Vedejs, E.; Wang, J. Abstracts of Papers, 212th National Meeting;
American Chemical Society: Washington, DC, 1996; ORGN 93.
A related benzofuranone synthesis using dimethyldioxirane
as the oxidant6 has been reported by Adam et al., and the
method has been applied to the diazonamide problem by
Moody et al.2c The latter study had targetted a regioisomeric
(4) Vedejs, E.; Barda, D. A. Org. Lett. 2000, 2, 1033.
(5) Nishiyama, H.; Isaka, K.; Itoh, K.; Ohno, K.; Nagase, H.; Matsumoto,
K.; Yoshiwara, H. J. Org. Chem. 1992, 57, 407.
(6) Adam, W.; Peters, K.; Sauter, M. Synthesis 1994, 111.
10.1021/ol005547x CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/24/2000

benzofuranone having the lactone ring attached to the C-17
oxygen, as in the hemiacetal ring of 1, and had used Black’s
C-acylation method7 to introduce an additional carbon
substituent at C-10. We had also planned to use the Black
procedure, but in our case, the substrate was the tyrosine-
derived lactone 10, and a chiral acylating agent 11 was used
for acylation.3 The chloroformate 11 was easily prepared
with 10 in the presence of triethylamine gave the enol
carbonate 12 in high yield, together with traces of the
isomeric 13. When 12 was treated with DMAP, a blue color
was observed, similar to that reported in a simpler case.7
The color faded on a time scale of hours, and nearly complete
conversion to 13 was observed in dichloromethane or in
THF. The latter conditions gave the best diastereomer ratio
of 3:1. Polar solvents such as acetonitrile produced lower
ratios, and so did the use of tributylphosphine as a replace-
ment for the DMAP catalyst. For preparative purposes, it
was best to isolate 12 by plug filtration over silica gel and
to dry the product over molecular sieves prior to the
rearrangement step. Addition of DMAP then gave a mixture
of 13 together with the diastereomer (not shown) in a 3:1
ratio, in 86% yield after 12 h at room temperature, and 13
was isolated by preparative HPLC in 60% yield from 10.
Crystals of 13 were obtained, but the material was not
suitable for X-ray structure determination. A similar acylation
sequence was therefore carried out from the benzofuranone
147 and the chloroformate 11. The key rearrangement from
the enol carbonate 15 was considerably faster than from 12
(ca. 2 min vs hours; DMAP/THF, rt) and significantly more
selective (8:1 16:17, 82%; major product assigned by X-ray
crystallography). On the basis of this evidence, the major
diastereomer 13 obtained from 10 was tentatively assigned
the same quaternary carbon configuration as in 16. After the
model study was completed, this assignment was confirmed
by an X-ray crystal structure of the minor diastereomer of
13.
Scheme 1
Scheme 2
Acknowledgment. This work was supported by the
National Institutes of Health (CA17918). The authors also
thank Mr. M. Zajac for performing the conversion from 10
to 13 and for preparing the minor isomer X-ray sample.
from the Whitesell alcohol, trans-(1R,2R)-2-phenylcyclo-
hexanol,8 by treatment with phosgene. Subsequent reaction
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(7) Black, T. H.; Arrivo, S. M.; Schumm, J. S.; Knobeloch, J. M. J.
Org. Chem. 1987, 52, 5425.
(8) Whitesell, J. K. Chem. ReV. 1992, 92, 953. King, S. B.; Sharpless,
K. B. Tetrahedron Lett. 1994, 35, 5611.
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Org. Lett., Vol. 2, No. 8, 2000