A photochemical entry to depsides: Synthesis of gustastatin

Article abstract of DOI:10.1021/ol047507p

(Chemical Equation Presented) Herein, we propose a modular and general strategy to construct orcinol-type depsides based on the photolysis of functionalized benzodioxinones (I). Notably, resorcinylic esters are obtained without competing isocoumarin (II) formation, exemplified by the first total synthesis of gustastatin in 10 steps from commercially available trihydroxybenzoic acid.

Full text of DOI:10.1021/ol047507p

ORGANIC
LETTERS
2005
Vol. 7, No. 4
685-688
A Photochemical Entry to Depsides:
Synthesis of Gustastatin
Jorge Garc´ıa-Fortanet, John R. Debergh, and Jef K. De Brabander*
Department of Biochemistry, UniVersity of Texas Southwestern Medical Center at
Dallas, 5323 Harry Hines BlVd., Dallas, Texas 75390-9038
jdebra@biochem.swmed.edu
Received December 4, 2004
ABSTRACT
Herein, we propose a modular and general strategy to construct orcinol-type depsides based on the photolysis of functionalized benzodioxinones
(I). Notably, resorcinylic esters are obtained without competing isocoumarin (II) formation, exemplified by the first total synthesis of gustastatin
in 10 steps from commercially available trihydroxybenzoic acid.
Many biologically active natural products contain an ortho-
functionalized salicylic or resorcinylic moiety. For example,
members of the macrocyclic salicylate family (cf., a)1 are
potent inhibitors of the mammalian vacuolar ATPase with a
potential novel mode-of-action,2 whereas resorcinylic mac-
rolides (cf., b) such as radicicol3 inhibit the molecular
chaperone Hsp90.4 Another class of resorcinylic natural
products, orcinol-type depsides, are composed of two (or
more) resorcinylic acid derivatives that carry identical or
different linear alkyl or 2-oxo-akyl chains.5 A recent example
is gustastatin (1), a compound isolated and characterized by
Pettit and co-workers from the stems and twigs of the
Brazilian nut tree GustaVia hexapetala.6 These depsides and
other lichen metabolites display a wide range of biological
activities, yet their therapeutic potential remains largely
unexplored.7
(1) For reviews, see: (a) Yet, L. Chem. ReV. 2003, 103, 4283-4306.
(b) Beutler, J. A.; McKee, T. C. Curr. Med. Chem. 2003, 10, 787-796.
(2) (a) Boyd, M. R.; Farina, C.; Belfiore, P.; Gagliardi, S.; Kim, J.-W.;
Hayakawa, Y.; Beutler, J. A.; McKee, T. C.; Bowman, B. J.; Bowman, E.
J. J. Pharmacol. Exp. Ther. 2001, 297, 114-120. (b) Xie, X.-S.; Padron-
Perez, D.; Liao, X.; Wang, J.; Roth, M. G.; De Brabander, J. K. J. Biol.
Chem. 2004, 279, 19755-19763.
In a recent communication, we disclosed a general method
for the synthesis of functionalized salicylates (III) under
essentially neutral conditions through photolysis of benzo-
dioxinones (I) [ eq 1, X ) H].8 The in situ generated quino-
(3) (a) Delmotte, P.; Delmotte-Plaque´e, J. Nature 1953, 171, 344. (b)
Mirrington, R. N.; Ritchie, E.; Shoppee, C. W.; Taylor, W. C.; Sternhell,
S. Tetrahedron Lett. 1964, 5, 365-370.
(4) Roe, S. M.; Prodromou, C.; O’Brien, R.; Ladbury, J. E.; Piper, P.
W.; Pearl, L. H. J. Med. Chem. 1999, 42, 260-266.
(5) For selected examples, see: (a) Santesson, J. Acta Chem. Scand. 1967,
21, 1162-1172. (b) Elix, J. A.; Venables, D. A.; Wedin, M. Aust. J. Chem.
1994, 47, 1335-1344. (c) Elix, J. A.; Wardlaw, J. H. Aust. J. Chem.2000,
53, 1007-1008.
(6) Pettit, G. R.; Zhang, Q.; Pinilla, V.; Herald, D. L.; Doubek, D. L.;
Duke, J. A. J. Nat. Prod. 2004, 67, 983-985.
(7) Mu¨ller, K. Appl. Microbiol. Biotechnol. 2001, 56, 9-16 and
references therein.
10.1021/ol047507p CCC: $30.25
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Published on Web 01/20/2005

Scheme 1
Figure 1. Photochemical approach to orcinol-type depsides.
ketenes (II)9 efficiently acylate a wide range of substrates,
including sterically hindered and base-sensitive alcohols that
are inert to other acylation methods.8 We envisioned that a
similar reaction modality could benefit the synthesis of
resorcinylic esters [ eq 1, X ) OR], an operation that is
sometimes difficult to achieve with more conventional
methods.10,11 Herein, we report the successful application of
our methodology to the first total synthesis of gustastatin
(1), an inhibitor of solid human tumor cell lines.
We designed a modular and general approach to the
orcinol-type depside system, creating opportunities to access
natural as well as designed members for further exploration.
Our underlying concept is based on the mild functional
group-tolerant photolysis of functionalized benzodioxinones
[ eq 1], appropriately sequenced according to the format
i); (2) optional functionalization of the liberated o-phenol
(step ii); (3) deprotection of the p-phenol (step iii); (4)
repeating this sequence with a liberated p-phenol A-ring
donor and benzodioxinone B-ring acceptor (steps i, iii, ii).
This concept was reduced to practice exemplified by the
synthesis of gustastatin (1) described below.
The synthesis of functionalized benzodioxinones com-
mences from cheap 2,4,6-trihydroxybenzoic acid 2 (Scheme
1). Condensation of this material with benzophenone, fol-
lowed by selective benzylation of the p-hydroxyl under
Mitsunobu12 conditions and triflation of the remaining
o-hydroxyl furnished benzodioxinone 3.13 Our next objective
entailed the introduction of the 2-oxo-heptyl chain, a feat
we failed to accomplish in one step via cross-coupling of
aryl triflate 3 with a methyl ketone enolate.14 Instead, we
resorted to an oxidative functionalization of the heptenyl
appendage in benzodioxinone 4, a compound conveniently
prepared by palladium-catalyzed cross-coupling of air-stable
and storable heptenyltrifluoroborate salt 7 (prepared from
1-heptyne as shown)15 with aryl triflate 3 under conditions
reported by Molander and Bernardi (80% yield).16 While
various attempts to functionalize the â-carbon of the styryl
shown in Figure 1: (1) irradiation of a protected p-hydroxy
benzodioxinone (ring A) in the presence of an alcohol (step
(8) Soltani, O.; De Brabander, J. K. Angew. Chem., Int. Ed. 2005,
accepted for publication.
(9) For the photochemical generation and characterization of nonsub-
stituted quinoketene in solution, see: Liu, R. C.-Y.; J. Lusztyk, McAllister,
M. A.; Tidwell, T. T.; Wagner, B. D. J. Am. Chem. Soc. 1998, 120, 6247-
6251.
(10) For selected recent examples of recorcinylic macrolide synthesis,
see: (a) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S.
J. J. Am. Chem. Soc. 2001, 123, 10903-10908. (b) Tichkowsky, I.; Lett,
R. Tetrahedron Lett. 2002, 43, 3997-4001 and 4002-4007. (c) Barluenga,
S.; Lopez, P.; Moulin, E.; Winssinger, N. Angew. Chem., Int. Ed. 2004,
43, 3467-3470.
(12) Mitsunobu, O. Synthesis 1981, 1-28.
(13) Dushin, R. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1992, 114,
655-659.
(11) For an elegant solution to benzofused resorcinylic macrolides via
de novo aryl synthesis from ynolides, see: Yang, Z.-Q.; Geng, X.; Solit,
D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc. 2004,
126, 7881-7889.
(14) (a) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818-11819. (b) Viciu, M. S.; Germaneau, R. F.; Nolan, S.
P. Org. Lett. 2002, 4, 4053-4056. (c) Review: Culkin, D. A.; Hartwig, J.
F. Acc. Chem. Res. 2003, 36, 234-245.
686
Org. Lett., Vol. 7, No. 4, 2005

Scheme 2
bond by hydroboration/oxidation or oxymercuration failed,
marin formation was also evident during the methylation of
the o-phenol in 9. Extensive experimentation revealed that
a reagent combination composed of Meerwein’s salt and
proton sponge was uniquely able to avoid the formation of
12/13, delivering desired methyl ether 10 as the only product
in 81% yield.21 Finally, hydrogenolytic debenzylation cleanly
liberated p-phenol 11.
a palladium-catalyzed epoxy-ketone rearrangement of styryl
epoxide 5 (4, pH 7 buffered mCPBA, 80%)17 provided the
desired â-ketone 6 as the only detectable isomer in 84%
yield.18 Consistent with the proposed oxidative addition/â-
hydride elimination mechanism,18 epoxide 5 was recovered
unchanged when treated with tributylphosphine alone under
otherwise identical reaction conditions.
The gustastatin B-ring substrate, benzodioxinone 14, was
prepared in two steps from common intermediate 6 via
debenzylation (H2, Pd/C, 90%) and methylation of the
liberated p-phenol with Meerwein’s salt and proton sponge
(95%).21 Irradiation (300 nm) of benzodioxinone 14 (2 equiv)
with p-phenol 11 (1 equiv) in dichloromethane completed
the synthesis of gustastatin (1), obtained in 71% isolated yield
(benzodioxinone 14 was recovered in 28%).22 This material
With an appropriately functionalized benzodioxinone at
hand, we next explored the potential of our photochemical
acylation methodology to assemble the depside gustastatin
(Scheme 2). The synthesis of the requisite A-ring methyl
resorcinylate 11 necessitated the photolysis of benzodioxi-
none 6 in the presence of methanol. When this reaction was
performed in dichloromethane (varying amounts of metha-
nol), the desired product 9 could be isolated in acceptable
yields between 53% and 81%, but substantial amounts of
3-methoxy-dihydroisocoumarin 8 were also produced under
these conditions. Changing the solvent to THF completely
suppressed the formation of this byproduct, and methyl
resorcinylate 9 was obtained in 89% yield.19 It is important
to mention that attempted formation of methyl benzoate 9
via conventional methanolysis (K2CO3, MeOH) only led to
isocoumarin formation (i.e., 12),20 underscoring the mild
conditions of the photochemical alternative.8 Facile isocou-
1
was identical to the natural product by IR, UV, H and 13C
NMR spectroscopy, and high-resolution mass spectrometry.
In summary, we have accomplished the first total synthesis
of the antitumor agent gustastatin in 10 steps (longest linear
sequence) from commercially available 2,4,6-trihydroxyben-
zoic acid. A key step in our approach involved a mild
photochemical formation of resorcinylic esters without
competing isocoumarin formation. This approach provides
the blueprint to a general and modular synthesis of natural
and unnatural orcinol-type depsides.
(15) (a) Hydroboration: Brown, H. C.; Bhat, N. G.; Somayaji, V.
Organometallics 1983, 2, 1311-1316. (b) KHF2 treatment: Vedejs, E.;
Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem.
1995, 60, 3020-3027.
(20) Isocoumarin formation is a common problem associated with o-(2-
oxo-alkyl)-substituted resorcinylates, requiring the use of masked ketones
in synthetic sequences. For selected examples, see: (a) Reference 10a. (b)
Elix, J. A.; Jayanthi, V. K. Aust. J. Chem. 1987, 40, 1851-1859. (c) Elix,
J. A.; Wardlaw, J. H. Aust. J. Chem. 1997, 4799-486.
(21) (a) Meerwein, H.; Hinz, G.; Hofmann, P.; Kronig, E.; Pfeil, E. J.
Prakt. Chem. 1937, 147, 257-285. (b) Evans, D. A.; Ratz, A. M.; Huff, B.
E.; Sheppard, G. S. Tetrahedron Lett. 1994, 35, 7171-7172.
(22) In principle, equimolar amounts of reactants could be employed,
although previous observations8 indicated that optimal yields are obtained
with an excess of one of the reactants. Optimization studies have not been
performed in this particular case.
(16) Molander, G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67, 8424-
8429.
(17) Imuta, M.; Ziffer, H. J. Org. Chem. 1979, 44, 1351-1352.
(18) Kulasegaram, S.; Kulawiec, R. J. J. Org. Chem. 1997, 62, 6547-
6561.
(19) Under these conditions, benzhydrol (34%) and diphenyl-(tetrahy-
drofuran-2-yl)-methanol (33%) were also isolated, resulting from photo-
chemistry of benzophenone, the stoicheometric byproduct from the initial
benzodioxinone photolysis.
Org. Lett., Vol. 7, No. 4, 2005
687

Acknowledgment. Financial support provided by the
Robert A. Welch Foundation and the National Institutes of
Health (CA 90349). J.G.-F. thanks the Spanish Ministry of
Education and Science for a FPU fellowship. J.K.D.B. is a
fellow of the Alfred P. Sloan Foundation.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for all new compounds and gustastatin (1). This material is
available free of charge via the Internet at http://pubs.acs.org.
OL047507P
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Org. Lett., Vol. 7, No. 4, 2005