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.
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