Synthesis of C(3) benzofuran-derived bisaryl quaternary centers: Approaches to diazonamide A

Article abstract of DOI:10.1021/ol006578v

(Equation Presented) Two complementary strategies for the synthesis of the diazonamide A bisaryl quaternary center are described. The first strategy relies upon an extremely facile tandem cyclopropanation/ring-opening sequence, which has proven amenable t

Full text of DOI:10.1021/ol006578v

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3521-3523
Synthesis of C(3) Benzofuran-Derived
Bisaryl Quaternary Centers:
Approaches to Diazonamide A
Douglas E. Fuerst, Brian M. Stoltz,† and John L. Wood*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity,
New HaVen, Connecticut 06520-8107
john.wood@yale.edu
Received September 11, 2000
ABSTRACT
Two complementary strategies for the synthesis of the diazonamide A bisaryl quaternary center are described. The first strategy relies upon
an extremely facile tandem cyclopropanation/ring-opening sequence, which has proven amenable to chiral catalysis to provide enantioenriched
material. The second strategy relies upon a more concise alkylation route ideal for material advancement.
Diazonamide A (1, Figure 1) is a secondary metabolite of
the colonial ascidian Diazona chinensis isolated off the coast
of the Philippines.1 In vitro, 1 exhibits potent activity against
human colorectal carcinoma and murine melanoma cancer
cell lines (IC50 < 15 ng/mL against HCT-116 and B-16).
Advanced testing and biological screening of 1, however,
have been limited by a lack of the natural material. Thus,
total synthesis is the only means available to access quantities
necessary for further testing.
Upon examination, 1 presents a number of interesting and
challenging structural features that include: the bisoxazole-
indole moiety, the bisaryl-substituted asymmetric quaternary
center C(10), and the rigid heterocyclic skeleton that holds
the molecule into a configuration possessing two atropiso-
meric axes (about the C(16)-C(18) and C(24)-C(29)
bonds). As a result of its unique structure and promising
biological activity, diazonamide A has generated significant
interest in recent years among the synthetic community.2 In
planning our synthesis of diazonamide A, we believed that
the three asymmetric sp3 centers on the left-hand macrocycle
(i.e., C(32), C(2), and C(10)) could be used to solve the more
difficult problem of controlling the axial chirality on the right
side of the molecule. This disconnection led us to focus our
attention on the preparation of esters 2a,b. Central to the
problem of constructing 2 is the introduction of the bisaryl
quaternary center, which represents C(10) in the natural
product. Herein we disclose the development of two comple-
mentary strategies for the construction of this challenging
carbon center in a diazonamide A model system.
Work commenced with commercially available hydroxy-
cinnamate 3, which was converted to allylic alcohol 4 via
(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.; Altra,
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) Jamison, T. F. Ph.D. Dissertation, Harvard University, Cambridge,
MA, 1997. (e) Boto, A.; Ling M.; Meek, G.; Pattenden, G. Tetrahedron
Lett. 1998, 39, 2223. (f) Wipf, P.; Yokokawa, F. Tetrahedron Lett. 1998,
39, 2223. (g) Jeong, S.; Chen, X.; Harran, P. G. J. Org. Chem. 1998, 63,
8640. (h) Hang, H. C.; Drotleff, E.; Elliott, G. I.; Ritsema, T. A.; Konopelski,
J. P. Synthesis 1999, 398. (i) Magnus, P.; Kreisberg, J. D. Tetrahedron
Lett. 1999, 40, 451. (j) Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000,
41, 831. (k) Chan, F.; Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000,
41, 835. (l) Chen, X.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2000,
39, 937. (m) Vedejs, E.; Wang. J. Org. Lett. 2000, 2, 1031. (n) Vedejs, E.;
Barda, D. A. Org. Lett. 2000, 2, 1033.
† Current address: Arnold and Mabel Beckman Laboratories of Chemical
Synthesis, Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasedena, CA 91125.
(1) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem.
Soc. 1991, 113, 2303.
10.1021/ol006578v CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/04/2000

Scheme 2
Figure 1. Retrosynthetic analysis.
formation of the benzyl ether and DIBAL reduction (Scheme
1).3 Subsequent bromination and alkylation of p-cresol
under transfer hydrogenation conditions proceeded in excel-
lent yield to deliver phenol 9. Treatment of 9 with the
N-hydroxysuccinimide ester 10 and NaH afforded R-diazo
ester 11.6 After much experimentation it was found that
cyclopropanation of 11 occurred with dirhodium(II) capro-
lactamate (Rh2(cap)4) in refluxing CH2Cl2 to give cyclopro-
pane 12.7 Unfortunately, conversion of 12 to ester 13
followed by treatment with BF3‚Et2O resulted in cleavage
of the undesired cyclopropane bond to furnish benzofuran
14. We believe this reaction proceeds by through-ring
scission of the cyclopropane followed by rearomatization.
In an effort to redirect the ring opening, we turned to a
substrate containing an alkoxy group at the C(2) position of
the benzofuran. To this end, benzofuran 8 was oxidized to
lactone 15 with peracetic acid (Scheme 3).2m After consider-
able experimentation it was found that 15 could be methyl-
ated in high yield to furnish a 1.7:1 ratio of the desired
O-alkylated benzofuran 17 and C-alkylated lactone 16,
respectively. Deprotection of the former to 18 followed by
acylation furnishes R-diazo ester 19. Decomposition of 19
with Rh2(cap)4 gave rise to the desired cyclopropane 20 in
excellent yield. With 20 in hand, attention focused on the
development of suitable conditions for cyclopropane ring
opening. To our delight, treatment of 20 with 3 equiv of
LiOMe led directly to ortho ester 22.8 This remarkable
cascade reaction, which unmasks the desired quaternary
center, likely proceeds via initial formation of ester 21
followed by opening of the cyclopropane.9 Overall, instal-
lation of the alkoxy group proved to be advantageous by
both improving the yield of the cyclopropanation reaction
and directing the rupture of the correct cyclopropane bond.
Scheme 1
furnished allyl ether 5, which underwent smooth ortho-
Claisen rearrangement to olefin 6.4 Reductive ozonolysis
followed by dehydration of the resulting hemiacetal 7
afforded benzofuran 8, a very versatile intermediate.
With 8 in hand we set out to explore formation of the
quaternary center via a cyclopropanation/ring-opening ap-
proach (Scheme 2).5 To this end, benzyl deprotection of 8
(3) The structure assigned to each to new compound is in accord with
its infrared and high-field 1H and 13C spectra, as well as appropiate parent
ion identification by high-resolution mass spectrometry.
(4) White, W. N.; Fife, W. K. J. Am. Chem. Soc. 1961, 83, 3846.
(5) Padwa, A.; Wisnieff, T. J.; Walsh, E. J. J. Org. Chem. 1989, 54,
299.
(6) Ouihia, A.; Rene, L.; Guilhelm, J.; Pascard, C.; Badet, B. J. Org.
Chem. 1993, 58, 1641.
(7) A second compound that appears to be the product of aryl C-H
insertion can also be isolated from the reaction mixture in 15% yield.
3522
Org. Lett., Vol. 2, No. 22, 2000

C(3)-alkylated lactone 23 in excellent yield. Importantly, this
product contains the same carbon-carbon connectivity and
oxidation states found in ortho ester 22. The convergent
nature of both approaches described herein to the quaternary
center should prove valuable in further studies directed
toward diazonamide A. Whereas the alkylation approach is
ideally suited for the advancement of material (four fewer
steps), the cyclopropanation/ring-opening sequence provides
a means of introducing asymmetry into the synthesis (Scheme
5). Preliminary work in this area has met with some success.
Scheme 3
Scheme 5
Treatment of R-diazo ester 19 with commercially available
Doyle’s catalyst under a single set of reaction conditions gave
rise to optically active cyclopropanated product 20 in 45%
ee.10,11
In summary, we have developed complementary cyclo-
propanation/ring-opening and alkylation strategies for the
construction of the bisaryl quaternary center present in
diazonamide A. Essential to both approaches was the
realization that the C(2) position of the ring system must be
in the acid oxidation state. Further efforts directed at the total
synthesis of diazonamide A in a fully functionalized system
are currently underway and will be reported in due course.
Central to the success of the aforementioned cyclopropa-
nation/ring-opening sequence was our recognition that the
C(2) position of the benzofuran must be in the acid oxidation
state. While not desired in the natural product, this increase
in oxidation levels led us to consider a complementary
alkylation approach to the quaternary center (Scheme 4). To
Acknowledgment. We are pleased to acknowledge the
support of this investigation by Bristol-Myers Squibb,
Yamanouchi, Pfizer, and Merck. J.L.W. is a fellow of the
Alfred P. Sloan Foundation.
Scheme 4
Supporting Information Available: Experimental and
spectral data pertaining to all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL006578V
(9) The intermediacy of compound 21 is supported by the isolation of
iii and its conversion to 22 upon treatment with BF3‚Et2O. The formation
and conversion of 21 can also be monitored by TLC analysis of the reaction
mixture.
this end, the enolate of lactone 15 was prepared as previously
described and treated with tert-butyl bromoacetate to afford
(8) Cyclopropane 20 can also be opened under acidic conditions (p-TsOH,
1 equiv) to give a 2:1 mixture of i and ii, respectively.
(10) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
(11) The enantioselectivty of this reaction was determined using the chiral
shift reagent Eu(hfc)3. At this time the absolute stereochemistry of 20 is
not known; 20 is only drawn as shown for illustrative purposes. For further
details see the Supporting Information.
Org. Lett., Vol. 2, No. 22, 2000
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