Total synthesis of (±)-mitorubrinic acid

Article abstract of DOI:10.1021/ol0610993

(±)-Mitorubrinic acid, a member of the azaphilone family of natural products, has been constructed in 12 steps. Key aspects of the synthesis include elaboration and oxidative dearomatization of an isocoumarin intermediate to provide the azaphilone nucleus

Full text of DOI:10.1021/ol0610993

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3481-3483
Total Synthesis of (±)-Mitorubrinic Acid
Maurice A. Marsini, Kristoffer M. Gowin, and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106
pettus@chem.ucsb.edu
Received May 4, 2006
ABSTRACT
(±)-Mitorubrinic acid, a member of the azaphilone family of natural products, has been constructed in 12 steps. Key aspects of the synthesis
include elaboration and oxidative dearomatization of an isocoumarin intermediate to provide the azaphilone nucleus with a disubstituted,
unsaturated carboxylic acid side chain.
The mitorubrins are a unique subclass of azaphilones isolated
from a variety of fungal species (Figure 1).1 The term
acid (4),3 and its supposed dimer, diazaphilonic acid (5).4
The molecules 1-4 only differ by the oxidation state of their
accompanying disubstituted E-olefinic side chain. They are
closely related to the lunatoic acid family of azaphilones,
which differ in their ester side chain functionality from the
mitorubrins.1b
Whalley and co-workers reported an 11-step synthesis of
(()-mitorubrin (1) some time ago.5 However, a resurgence
of interest accompanied recognition by the synthetic com-
munity of the diverse and distinct biological activities
exhibited by the azaphilones. In particular, mitorubrinic acid
(4) induces formation of chlamydospore-like cells in fungi
and inhibits trypsine with an IC50 of 41 µmol/L.3b On the
other hand, its presumed dimer diazaphilonic acid (5) inhibits
Tth DNA polymerase with an IC50 of 2.6 µg/mL and is
reported to completely inhibit MTI (human leukemia)
telomerase activity at 50 µM.4
Figure 1. The mitorubrins.
azaphilone arises from the affinity of the 4H-pyran nucleus
to undergo substitution with primary amines to form the
corresponding vinylogous 4-pyridones. The mitorubrin sub-
class of azaphilones is comprised of (-)-mitorubrin (1),2 (-)-
mitorubrinol (2),2 (-)-mitorubrinal (3),1 (-)-mitorubrinic
Porco has reported a concise entry to many azaphilone
scaffolds using a gold-mediated cycloisomerization of o-
(3) (a) Locci, R.; Merlini, L.; Nasini, G.; Locci, J. R. Giornale di
Microbiologia 1967, 15, 93. (b) Lesova, K.; Sturdikova, M.; Rosenberg,
M. J. Basic Microbiol. 2000, 40, 365. (c) Steglich, W.; Klaar, M.; Furtner,
W. Phytochemistry 1984, 18, 2874.
(4) (a) Tabata, Y.; Ikegami, S.; Yaguchi, T.; Sasaki, T.; Hoshiko, S.;
Sakuma, S.; Shin-Ya, K.; Seto, H. J. Antibiot. 1999, 52, 412. (b) Oikawa,
H.; Tokiwano, T. Nat. Prod. Rep. 2004, 21, 321.
(1) (a) Suzuki, S.; Hosoe, T.; Nozawa, K.; Yaguchi, T.; Udagawa, S.;
Kawai, K. J. Nat. Prod. 1999, 62, 1328. (b) Natsume, M.; Takahashi, Y.;
Marumo, S. Agric. Biol. Chem. 1985, 49, 2517.
(2) (a) Bu¨chi, G.; White, J. D.; Wogan, G. N. J. Am. Chem. Soc. 1965,
87, 3484. (b) Steyn, P. S.; Vleggaar, R. J. Chem. Soc., Perkin Trans. 1
1975, 204.
(5) Whalley, W. B.; Chong, R.; Gray, R. W.; King, R. R. J. Chem. Soc.
C 1971, 3571.
10.1021/ol0610993 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/07/2006

alkynyl benzaldehydes.6a More recently, he provided enan-
tioselective access to several azaphilones using stoichiometric
copper, O2, and (-)-sparteine and has applied the method
in the synthesis of the azaphilone (-)-S-15183A.7 However,
the gold-mediated cyclization and subsequent copper-medi-
ated enantioselective oxidation may not be amenable to
derivatives containing an acrylate or disubstituted olefin, such
as that found in the mitorubrins.
Scheme 2. A Concise Route to the Azaphilone Core
Therefore, we set out to devise a racemic route to the
mitorubrins, which might be eventually adapted to our
enantioselective dearomatization protocol.8 The fully elabo-
rated skeleton 6 of the mitorubrins arises upon attaching
orsellinic acid 7 to the 3° alcohol of 8 (Scheme 1).9 We
Scheme 1. General Synthetic Strategy to Address the
Mitorubrins
imagined that the azaphilone core 8, in turn, could arise from
the isocoumarin 9. Recognizing that an analogue of isocou-
marin 9 had been produced by Staunton’s orsellenate
enolization protocol some time ago,10 we chose the methyl
benzoate 10 as our starting material.
yield. The four-step sequence from 10 to 14 can easily be
carried out on multigram scale.
Selective reduction of the isocoumarin carbonyl moiety
in 14 with 1.05 equiv of diisobutylaluminum hydride
(DIBAL-H) in tetrahydrofuran followed by global depro-
tection of the O-tert-butyl carbonate and O-(CH2)2TMS
ethers with zinc bromide in nitromethane provides the keto
aldehyde 15 in 69% overall yield. The 2-benzopyrylium salt
16 forms upon addition of acetic acid and p-toluenesulfonic
acid (p-TsOH) to the keto aldehyde 15.11 After concentration
and evaporation of the solvent, the salt 16 is re-dissolved in
1,2-dichloroethane and stirred with o-iodoxybenzoic acid
(IBX) and a catalytic amount of tetra-n-butylammonium
iodide (TBAI) to afford the azaphilone 17 in 57% yield. The
delivery of a hydroxy residue ortho to both phenols was
expected based on our earlier work with IBX.12 However,
an important modification, addition of TBAI as reported by
Porco, proved critical for this nucleus.6
Our synthesis begins with mono-phenol protection using
di-tert-butyl dicarbonate, N-ethyldiisopropylamine (DIPEA),
and 4-(dimethylamino)pyridine (DMAP). Coupling of the
more congested phenol proceeds with 2-(trimethylsilyl)-
ethanol under Mitsunobu’s conditions. This two-pot sequence
affords the differentially protected ester 11 in 92% overall
yield (Scheme 2). Addition of lithium diisopropylamide
(LDA) results in γ-deprotonation and formation of the
corresponding dienic enolate, which resembles a dimethide.10
However, a slight amendment to Staunton’s conditions
proved necessary. Introduction of N,N,N′,N′-tetramethyleth-
ylenediamine prior to the Weinreb acetamide 12 provides
the keto ester 13 in 81% yield, whereas yields were 40-
50% in its absence. Addition of base promotes enolization
and cyclization of 13 to afford the isocoumarin 14 in 98%
Having satisfactorily tested the dearomatization protocol,
we began the synthesis of (()-mitorubrinic acid (4) in
earnest. Starting from isocoumarin 14, allylic oxidation with
(6) (a) Zhu, J.; Germain, A. R.; Porco, J. A. Angew. Chem., Int. Ed.
2004, 43, 1239. (b) Stark, L. M.; Pekari, K.; Sorensen, E. J. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 12064.
(7) Zhu, J.; Grigoriadis, N. P.; Lee, J. P.; Porco, J. A. J. Am. Chem. Soc.
2005, 127, 9342.
(8) Mejorado, L.; Hoarau, C.; Pettus, T. R. R. Org. Lett. 2004, 6, 1535.
(9) Solladie, G.; Rubio, A.; Carren˜o, M. C.; Ruano, J. L. G. Tetrahedron:
Asymmetry 1990, 3, 187.
(11) For acid-catalyzed formation of benzopyrylium salts, see: (a) Wei,
W.; Yao, Z. J. Org. Chem. 2005, 70, 4585. (b) Suzuki, T.; Okada, C.; Arai,
K.; Awaji, A.; Shimizu, T.; Tanemura, K.; Horaguchi, T. J. Heterocycl.
Chem. 2001, 38, 1409. (c) Selenski, C. S.; Pettus, T. R. R. Tetrahedron
2006, 62, 5298.
(12) Magzdiak, D.; Rodriguez, A. A.; Van de Water, R. V.; Pettus, T.
R. R. Org. Lett. 2002, 4, 285.
(10) Lewis, C. N.; Spargo, P. L.; Staunton, J. Synthesis 1986, 944.
3482
Org. Lett., Vol. 8, No. 16, 2006

selenium dioxide in anhydrous dioxane affords the corre-
sponding 3-formyl isocoumarin intermediate.13 Homologation
using (t-butoxycarbonylmethylene)triphenylphosphorane in
methylene chloride gives a 69% overall yield of E-tert-butyl
ester 18, along with a small amount of its corresponding
Z-isomer that is easily removed by chromatography. DIBAL-H
in THF selectively reduces the lactone moiety, and the tert-
butyl ester emerges unscathed. Addition of acidic methanol
to the hemi-ketal intermediate followed by desilylation with
tetra-n-butylammonium fluoride (TBAF) yields the mono-
O-Boc phenol 19 in 80% over the three steps. Because of a
mentation, we find that the ketal 19 converts to the
benzopyrylium salt 20 when dissolved in a 20:1 mixture of
1,2-dichloroethane and trifluoroacetic acid at 0 °C. Upon
subsequent exposure to IBX/TBAI,6a,12 the azaphilone 21 is
produced in a modest yet reproducible 40% yield. The
azaphilone 23 also directly arises from reaction of ketal 19
with iodosylbenzene and Lewis acids, such as trimethylsilyl
trifluoromethanesulfonate or BF3•OEt2. However, these
conditions prove capricious (5-54%) and in some instances
result in accompanying tert-butylation of the azaphilone
nucleus.
Nevertheless, with a modest amount of the fully function-
alized azaphilone core in hand, our attentions turned toward
esterification. Several protocols were examined. Most condi-
tions failed in our hands. In particular, photolysis of 21 with
an orsellenate-derived benzodioxin (23) using De Braband-
er’s14 protocol proved ineffective due to decomposition of
the azaphilone. However, Yamaguchi’s lactonization condi-
tions using 2,4,6-trichlorobenzoyl chloride, acid 22, and NEt3
produces the desired ester in a 35% yield.15 Subsequent
global cleavage of the tert-butyl ester and tert-butyl carbon-
ates proceeds with 3 M HCl in refluxing dioxane over 4 h
to afford (()-mitorubrinic acid (4) in a 31% yield over the
two steps.
Scheme 3. Completion of (()-Mitorubrinic Acid (4)
In conclusion, the first total synthesis of (()-mitorubrinic
acid (4) has been completed. The target is obtained in 12
steps in 5% overall yield. The core 21 is accessible in 16%
yield after 10 steps. Although the congested esterification
with the acid 22 needs further optimization (35% yield), the
final deprotection proceeds in nearly quantitative fashion.
We are currently examining the intramolecular cycloaddition
of the symmetric anhydride derived from 4 to address
diazaphilonic acid (5), as well as an enantioselective synthesis
of (-)-4. Our findings will be reported shortly.
Acknowledgment. We are thankful for financial support
provided by the NIH GM-64831 and U.S. Army Medical
Research and Material Command (M.A.M.) (DAMD17-02-
1-0334). M.A.M. thanks the University of California at Santa
Barbara for a Graduate Mentor Fellowship.
Supporting Information Available: Full experimental
details and compound characterization (1H NMR, 13C NMR,
HRMS, FT-IR). This material is available free of charge via
the Internet at http://pubs.acs.org.
problematic selective O-Boc cleavage in the presence of the
tert-butyl ester, we decided to oxidize 19. Given our previous
finding shown in Scheme 2, the oxidative dearomatization
of 19 proved surprisingly difficult. This problem stems from
competitive tert-butylation of the azaphilone by acidic
cleavage of the O-Boc moiety. After considerable experi-
OL0610993
(14) Soltani, O.; De Brabander, J. Angew. Chem., Int. Ed. 2005, 177,
1724.
(13) Modi, A. R.; Nadkarni, D. R.; Usgaonkar, R. N. Ind. J. Chem. 1979,
17B, 624.
(15) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
Org. Lett., Vol. 8, No. 16, 2006
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