Studies on the synthesis of furanosteroids. I. Viridin models

Article abstract of DOI:10.1021/ol061697h

Alkyne oxazoles of general structure I are transformed directly to furo[2,3-b]phenol derivatives II by a sequence involving intramolecular Diels-Alder/retro-Diels-Alder reaction followed by tautomerization. Suitably functionalized phenols II undergo an intramolecular phenol-dienone-aldol condensation, generating the A,B,E-ring skeleton III characteristic of the viridin (1) class of furanosteroids.

Full text of DOI:10.1021/ol061697h

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4125-4128
Studies on the Synthesis of
Furanosteroids. I. Viridin Models
E. Hampton Sessions and Peter A. Jacobi*
Department of Chemistry, Dartmouth College, HanoVer, New Hampshire 03755
p.jacobi@dartmouth.edu
Received July 10, 2006
ABSTRACT
Alkyne oxazoles of general structure I are transformed directly to furo[2,3-b]phenol derivatives II by a sequence involving intramolecular
Diels Alder/retro-Diels Alder reaction followed by tautomerization. Suitably functionalized phenols II undergo an intramolecular phenol
dienone aldol condensation, generating the A,B,E-ring skeleton III characteristic of the viridin (1) class of furanosteroids.
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The furanosteroids are a class of novel pentacyclic fungal
metabolites that share in common a furan ring, bridging
positions 4 and 6 of the steroid skeleton (Figure 1).1 Members
and more recently because of their ability to selectively block
certain intracellular signaling pathways associated with cell
growth and development.2b,c As such, they have potential as
new therapeutic agents for diseases characterized by rapid
cell proliferation, including cancer. Prominent members
include those of the viridin (1) and wortmannin (2) families,
which owe their growth inhibitory properties to their activity
as irreversible inhibitors of phosphoinositide 3-kinase (PI3K),1
a class of enzymes that play a key role in important cell
signaling processes.2b,c Structure-activity studies have iden-
tified C20 in both 1 and 2 as a crucial site for PI3-kinase
inhibition, most likely due to the highly electrophilic nature
of the furan ring.2d It has been postulated that irreversible
inhibition occurs by nucleophilic addition of the kinase to
C
20 (arrows),2e a process that is facilitated by the C3 and C7
carbonyl groups. In vitro studies support this premise because
both amines and thiols rapidly open the furan ring.2d
(2) (a) Brian, P. W.; McGowan, J. C. Nature (London) 1945, 156, 144.
(b) Powis, G.; Bonjouklian, R.; Berggren, M. M.; Gallegos, A.; Abraham,
R.; Ashendel, C.; Zalkow, L.; Matter, W. F.; Dodge, J. Cancer Res. 1994,
54, 2419. (c) Ward, S.; Sotsios, Y.; Dowden, J.; Bruce, I.; Finan, F. Chem.
Biol. 2003, 10, 207 and cited references. See also 1b. (d) Norman, B. H.;
Shih, C.; Toth, J. E.; Ray, J. E.; Dodge, J. A.; Johnson, D. W.; Rutherford,
P. G.; Schultz, R. M.; Worzalla, J. F.; Vlahos, C. J. J. Med. Chem. 1996,
39, 1106. (e) Wymann, M. P.; Bulgarelli-Leva, G.; Zvelebil, M. J.; Pirola,
L.; Vanhaesebroeck, B.; Waterfield, M. D.; Panatotou, G. Mol. Cell. Biol.
1996, 16, 1722. (f) Liu, Y.; Shreder, K. R.; Gai, W.; Corral, S.; Ferris, D.
K.; Rosenblum, J. S. Chem. Biol. 2005, 12, 5256.
Figure 1. Furanosteroid class of PI3-kinase inhibitors.
of this class have attracted attention for many years because
of their potent antiinflammatory and antibiotic properties2a
(1) For reviews, see: (a) Hanson, J. R. Nat. Prod. Rep. 1995, 12, 381.
(b) Wipf, P.; Halter, J. H. Org. Biomol. Chem. 2005, 3, 2053.
10.1021/ol061697h CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/04/2006

However, only a small number of analogues have been
successfully prepared to test this hypothesis in vivo.
Progress in this area has been slow because of the many
difficulties associated with synthesizing these compounds.3
Despite efforts spanning over two decades, only one very
recent total synthesis of 1 has been reported,3m along with
two syntheses of 2 (one de novo).3b,d The furanosteroid
skeleton itself has also proven to be a significant synthetic
challenge. Recently, we began a program exploring a
fundamentally new approach to synthesizing members of the
viridin (1) and wortmannin (2) families, involving bond
disconnection at C1-C10 (cf. dashed lines in Figure 1). Our
synthetic analysis for viridin and related furanosteroids is
shown in Scheme 1.
C1-epimerization. However, to the best of our knowledge,
the C1 R-epimer of 3 does not occur naturally. On this basis,
we reasoned that if such an equilibrium exists it must strongly
favor the ring-closed product 3 as well as the “natural” syn
stereochemistry at C1-C10. It followed that 4 constituted an
attractive synthetic precursor to 3.
In our synthetic planning, we assumed that the phenol ring
in 4 has little aromatic character, analogous to the case with
anthracen-10-ol and related species.4 Otherwise, it would be
difficult to rationalize the stability of compounds such as 3.
Also, in the transformation of 4 to 3, we expected that the
desired syn stereochemistry at C1-C10 would predominate
under kinetic control due to a more favorable Burgi-Dunitz
trajectory angle (vide infra).5 The overriding issue pertained
to the synthesis of 4 itself, which we hoped to accomplish
employing the alkyne oxazole Diels-Alder (DA) methodol-
ogy we have used in the syntheses of numerous naturally
occurring furans, butenolides, and lactones.6 Thus, DA/retro-
DA reaction of 7 was expected to lead directly to furan 5,
which upon tautomerization would afford the desired phenol
4 (Scheme 1). To test this approach, we have been investi-
gating the synthesis and reactivity of simpler alkyne oxazoles
of type 8, focusing on their conversion to viridin model
systems 9 incorporating the characteristic skeletal features
of 1 (Scheme 2).
Scheme 1. Viridin Synthetic Analysis
Scheme 2. Proposed Viridin Model Studies
We pursued a number of routes for the synthesis of alkyne
oxazoles 8. Ultimately, however, we made use of the inno-
vative methodology of Pettus et al., who developed a general
procedure for converting salicylaldehyde derivatives to a
wide variety of o-substituted phenols.7a This is illustrated in
Scheme 3 for the parent compound 10, which in step 1 is
converted to the Boc derivative 11. Next, in a very efficient
sequence, treatment of 11 with 1.05 equiv of MeLi generated
the reactive o-quinone methide 12, by a pathway involving
nucleophilic addition to the aldehyde, followed by intramo-
lecular transfer of the Boc group and 1,4-elimination (not
shown). Quenching with the Grignard reagent derived from
trimethylsilylacetylene (TMSA) followed by triflation then
gave a 74% overall yield of the desired triflate derivative
14 on 95 mmol scales (>20 g). With ample quantities of 14
A distinguishing feature of the viridin skeleton 3 is that
the C1-C10 bond can be formally derived by intramolecular
aldol condensation of phenol aldehydes 4 (Scheme 1; not
the biogenetic pathway). Viewed in this context, it is
interesting that 3 and related materials do not at least partly
revert to 4 via retro-aldol reaction, providing a pathway for
(3) Representative studies. Wortmannin family: (a) Broka, C. A.;
Ruhland, B. J. Org. Chem. 1992, 57, 4888. (b) Sato, S.; Nakada, M.;
Shibasaki, M. Tetrahedron Lett. 1996, 37, 6141. (c) Honzawa, S.; Mizutani,
T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 311. (d) Mizutani, T.;
Honzawa, S.; Tosaki, S.-y.; Shibasaki, M. Angew. Chem., Int. Ed. 2002,
41, 4680. (e) Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053 and
cited references. Viridin family: (f) Moffatt, J. S. J. Chem. Soc. (C) 1966,
734. (g) Yasuchika, Y.; Kenji, H.; Kanematsu, K. Chem. Commun. 1987,
515. (h) Carlina, R.; Higgs, K.; Older, C.; Randhawa, S.; Rodrigo, R. J.
Org. Chem. 1997, 62, 2330. (i) Souza, F. E. S.; Rodrigo, R. Chem. Commun.
1999, 1947. (j) Boynton, J.; Hanson, J. R.; Kiran, I. J. Chem. Res. (S) 1999,
638. (k) Wright, D.; Whitehead, C.; Orugunty, R. Abstracts of Papers, 221st
ACS National Meeting, 2001; American Chemical Society: Washington,
DC. (l) Wright, D. L.; Robotham, C. V.; Aboud, K. Tetrahedron Lett. 2002,
43, 943. (m) Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew.
Chem., Int. Ed. 2004, 43, 1998.
(4) Freiermuth, B.; Hellrung, B.; Peterli, S.; Schultz, M.-F.; Wintgens,
D.; Wirz, J. HelV. Chim. Acta 2001, 84, 3796.
(5) Burgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153.
(6) For leading references, see: Jacobi, P. A.; Lee, K. J. Am. Chem.
Soc. 2000, 122, 4295.
(7) (a) Van De Water, R. W.; Magdziak, D. J.; Chau, J. N.; Pettus, T. R.
R. J. Am. Chem. Soc. 2000, 122(27), 6502. (b) We are grateful to Mr. Roger
O’Connor of these laboratories for optimizing this step.
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Org. Lett., Vol. 8, No. 18, 2006

Scheme 3. Synthesis of Model Alkyne Oxazoles 8
Scheme 4. Preliminary Thermolysis Studies
8c was transformed to a mixture of 18c-21c, in a combined
yield of 59% at 73% conversion (cf. Scheme 4). The forma-
tion of 20c and 21c could be lessened by thorough degassing
and employing antioxidants. Usually, though, we found it
expeditious to allow oxidation to proceed because both 20c
and 21c functioned as convenient and stable sources of the
parent phenol 19 and related derivatives. For example, em-
ploying 20c, we were able to prepare the saturated ester
derivative 23 by a simple two-step sequence consisting of
catalytic hydrogenation (20c f 22),8 followed by regenera-
tion of the parent phenol (Et3SiH, BF3‚Et2O) and in situ
silylation (Scheme 5). The identical sequence could be
in hand, we developed a straightforward three-step sequence
leading to the alkyne oxazole 8a, consisting of (1,2) elabor-
ation to the corresponding boronic acid 17 (not shown)7b and
(3) Suzuki coupling with the readily prepared acid chloride
15 (average yield ∼ 80% per step). Finally, for the purpose
of additional functionalization, the initially produced TMS-
alkyne 8a was desilylated to 8b with K2CO3/MeOH (97%).
Among other examples, this last material then afforded
alkyne oxazoles 8c,d using standard coupling techniques.
Upon thermolysis (140-170 °C), alkyne oxazoles 8a-d
were converted to variable mixtures of four Diels-Alder
derived products, identified as dienones 18, phenols 19, and
the oxidized products 20 and 21 (28-67% combined yields,
not optimized).8 A detailed study of this reaction provided
information on the source of each compound. As expected,
dienones 18 are the primary reaction products, and they are
reasonably stable in the absence of air or acid impurities.
On acidic workup, however, dienones 18 undergo equilibra-
tion with the corresponding phenols 19, which proved to be
extremely sensitive to oxidation even at ambient tempera-
ture. This conversion produced directly the tertiary alcohols
20, which on thermolysis gave the quinone methides 21.
Initially, we were surprised to find that tautomers 18 sur-
vived the reaction conditions. However, a search of the
literature revealed that this phenomenon is quite common,
as, for example, in various furanoeremophilanes isolated from
the Psacalium and Senecio genera.9a-c Most likely, such
tautomers are also stabilized by relief of peri-interactions.
In any event, this finding gave us additional confidence that
the eventual closure of ring A would be thermodynamically
favored.
Scheme 5. Preparation of a Viridin (1) Model
Our viridin model studies made use of the alkyne oxazole
8c (Scheme 4, R ) cis-HCdCHCO2Et), which was prepared
in 63% yield by Sonogashira coupling of 8b (R ) H) with
ethyl cis-iodoacrylate.9d Upon heating in o-xylene (140 °C),
applied with equal efficiency to mixtures of 20c and 21c.
DIBAH reduction of 23 then afforded a nearly quantitative
Org. Lett., Vol. 8, No. 18, 2006
4127

yield of aldehyde 24, which was a suitable substrate for
testing the formation of ring A. Having at this point reached
the “moment of truth”, we were pleased to find that 24
cleanly underwent the desired ring closure, producing with
TiCl4/CH2Cl2 a 75% yield of viridin models 25-syn and
25-anti with 4:1 stereoselectivity. Under these conditions,
no evidence was found for equilibration between 25-syn and
25-anti nor for retro-aldol cleavage to give back 24.
We took special care in assigning the structures of 25-syn
and 25-anti because this transformation strongly supports the
viability of our proposed syntheses of viridin (1) and related
species. In addition to detailed NOE studies, which fully
corroborated the structure of 25-syn, the isomeric alcohols
25-syn and 25-anti have a tell-tale signature in their NMR
spectra not previously described (Figure 2; cf. also Support-
ing Information). As in viridin (1) itself, H11 in 25-syn resides
in the deshielding zone of the C1-hydroxyl group (nearly
coplanar), and it’s signal is shifted dramatically downfield
(8.31 ppm). In contrast, the corresponding signal in 25-anti
is found at 7.63 ppm. A nearly identical chemical shift
difference is observed for H11 in the closely related epimeric
alcohols 26-syn and 26-anti, prepared by Sorensen et al. in
their synthesis of 1.3m,10 Finally, acylation of 25-syn gave a
crystalline acetate derivative 25-syn-Ac, whose structure was
confirmed by X-ray analysis.8
We are confident the conversion of 24 to 25-syn can be
optimized to both higher yields and selectivities, and we
expect ultimately to effect transformations of the type 7 f
3 in a single step (cf. Scheme 1). Total syntheses of 1 and
2 employing this methodology are under investigation.
Acknowledgment. E.H.S. (Dartmouth College) was the
recipient of a National Science Foundation Predoctoral
Fellowship during portions of this work.
Supporting Information Available: Experimental and
NMR spectra for all new compounds. X-ray crystal structures
Figure 2. NMR spectra of viridin models 25-syn and 25-anti.
(8) The structures of 22 and 25S-Ac were confirmed by X-ray analysis.
We are grateful to Mr. Benjamin E. Kucera and Dr. Victor G. Young, Jr.,
of the X-ray Crystallographic Laboratory of the University of Minnesota,
Minneapolis, MN, for performing these analyses.
(9) (a) Garduno-Ramirez, M. L.; Trejo, A.; Navarro, V.; Bye, R.; Linares,
E.; Delgrado, G. J. Nat. Prod. 2001, 64, 432. (b) Torres, P.; Chinchilla, R.;
Asensi, M. C.; Grande, M. Phytochemistry 1989, 28, 3093. (c) Burgueno-
Tapia, E.; Bucio, M. A.; Rivera, A.; Joseph-Nathan, P. J. Nat. Prod. 2001,
64, 518. (d) Sonogashira, K. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed; Wiley-Interscience: New York,
2002.
for 22 and 25-syn-Ac. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL061697H
(10) We are grateful to Mr. Erik Alexanian of Professor Sorensen’s group
for providing us with these spectra (compounds 16 and epi-16 in ref 3m).
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