A R T I C L E S
Yang et al.
Scheme 1. Our First Total Synthesis of Cycloproparadicicol
Scheme 2. New Ynolide Approach for Cycloproparadicicol
that the epoxide both in radicicol and in radicicol oxime (which
is active in in vivo models10) could well be a source of
nonspecific cytotoxicity, which could narrow the exploitable
margin of therapeutic index. Furthermore, the potential chemical
vulnerability of the dienyl epoxide raised concerns about drug
shelf stability as well as pharmacokinetics. With a view to
molecular editing, of the oxido function in a setting of minimal
conformational perturbation of the radicicol lead, we were drawn
to analogue 2 in which the epoxide linkage is replaced by a
cyclopropane.
based on early investigations of biological profiles, cyclopro-
paradicicol now emerges as a candidate for full scale preclinical
evaluation.
We had previously shown that compound 2 has an in vitro
biological profile comparable to that of 1.11 Moreover, we
brought to bear an important line of evidence that 2 and 1 were
closely related in their interactions with their biotargets. Thus
changes in peripheral stereogenic centers in both 1 and 2 bring
about the same consequences in biological function. In other
words, both structures as shown are optimized from a stereo-
chemical perspective. Moreover, and of considerable potential
advantage for radicicol-based inhibitors, they also display
cytotoxicity against Rb (retinoblastoma)-negative cells known
to be resistant to 17AAG.11
These promising findings inevitably raised issues as to the
availability of cycloproparadicicol. Clearly, our first synthesis
of this compound,11 while touching on several issues of
academic interest in organic chemistry, did not seem promising
for producing more than token amounts of the now interesting
2.
As seen, the first synthesis from our lab relied on the
appropriate sequenced Mitsunobu esterification, dithiane alky-
lation, and ring closing olefin metathesis. While highly con-
vergent and concise, this first generation pathway to radicicol
suffered from several low yielding steps which did not improve
following attempted optimization. In particular, the low yields
associated with the dithiane alkylation and ring-closing metath-
esis (RCM) steps sharply curtailed access to cycloproparadicicol
for evaluation.11
Indeed, a new strategy has been formulated and reduced to
practice, resulting in a much improved second generation total
synthesis of cycloproparadicicol.12 In addition, the new route
shows promise of applicability to a broad range of resorcinylic
macrolides.13 Herein, we disclose the full details of this new
approach and its application to reach cycloproparadicicol as well
as aigalomycin D. The synthesis and biological activities of a
number of interesting analogues of cycloproparadicicol will be
described. Based on the much improved route of synthesis, and
Results and Discussions
Overall Strategy. The defining element of our second
generation strategy was the building of the aromatic sector of
the resorcinylic marcrolide by Diels-Alder reaction of a new
type of dienophile, i.e., an “ynolide”. This cycloaddition route
to the benzo-fused macrolactone represents a substantial de-
parture from the usual mode of synthesis in which one starts
with an aromatic ring and appends to it suitable arms to close
the macrolactone ring (cf. Schemes 1 and 2). We hoped that
the new ynolide approach, if successful, would be highly
convergent and would allow for rapid access to a broad family
of resorcinylic macrolides. Since it has been our experience that
monoactivated acetylenic dienophiles are surprisingly weakly
reactive in Diels-Alder reactions,14 the success of a projected
Diels-Alder cycloaddition aromatization sequence could not
have been anticipated with confidence.
Synthesis of Acyclic Alkynoic Ester. To facilitate progress
to the key issues of the plan, we sought to develop an efficient
synthesis route to reach a seco-alkynoate ester, which, following
RCM, would afford the ynolide dienophile. In practice, the
synthesis commenced with commercial 2,4-hexadienal (sorbal-
dehyde, 6, Scheme 3). Reformatsky-like condensation of pro-
pargyl bromide (5) with 6 led to the expected carbinol.
Following â-esterification, alkyne precursor 7 was in hand in
good yield.15,16 Treatment of 7 with n-butyllithium generated
an alkynide ion, which was carboxylated with dry ice, to provide
acid 8, in very high yield.17 Following reaction of racemic 8
and the known optically pure and defined alcohol 918 under
Mitsunobu conditions,19 ester 10 was obtained as a diastereo-
meric mixture at the future C2′.
(14) Danishefsky, S.; Etheredge, S. J. J. Org. Chem. 1979, 44, 4716-4717.
(15) Friedrich, L. E.; De Vera, N.; Hamilton, M. Synth. Commun. 1980, 10,
637-643.
(16) Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Org. Chem. 1996, 61,
1082-1100.
(10) Agatsuma, T.; Ogawa, H.; Akasaka, K.; Asai, A.; Yamashita, Y.; Mizukami,
T.; Akinaga, S.; Saitoh, Y. Bioorg. Med. Chem. 2002, 10, 3445-3454.
(11) Yamamoto, K.; Garbaccio, R. M.; Stachel, S. J.; Solit, D. B.; Chiosis, G.;
Rosen, N.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 1280-
1284.
(12) Yang, Z.-Q.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 9602-9603.
(13) Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413-416.
(17) Fuganti, C.; Pedrocchi-Fantoni, G.; Sarra, A.; Servi, S. Tetrahedron:
Asymmetry 1994, 5, 1135-1138.
(18) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J.
Am. Chem. Soc. 2001, 123, 10903-10908.
(19) Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.; Sun,
L.; Akhiezer, A.; Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237-12254.
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7882 J. AM. CHEM. SOC. VOL. 126, NO. 25, 2004