inhibit trypsin (IC50 ) 41 µM).2b The dimeric azaphilone
diazaphilonic acid (2) inhibits Tth DNA polymerase (IC50
) 2.6 µg/mL) and MTI (human leukemia) telomerase
(complete inhibition at 50 µM).3a
Scheme 1. Synthesis of (-)-Mitorubrin 1a
Because of the interesting structural features and biological
properties of mitorubrin and related azaphilones, a number
of synthetic studies have been disclosed. In the early 1970s,
Whalley and co-workers reported a synthesis of (()-
mitorubrin (1a).6 Recently, a synthesis of (()-mitorubrinic
acid was reported by Pettus and co-workers.7 As part of our
synthetic studies toward the azaphilones, our laboratory has
developed a racemic route employing gold(III)-mediated
cycloisomerization of alkynylbenzaldehydes.8 More recently,
we reported an asymmetric synthesis of the azaphilone core
involving copper-mediated oxidative dearomatization.9 In this
Communication, we describe syntheses of (-)-mitorubrin and
related natural products employing enantioselective oxidative
dearomatization methodology to rapidly assemble the aza-
philone core and olefin cross-metathesis to install the
requisite side chains from a common intermediate.
Our retrosynthesis of (-)-mitorubrin and related natural
products is outlined in Figure 2. Natural products varying
desilylation, afforded alkynylbenzaldehyde 7 (Scheme 1).11
A second Sonogashira coupling of 7 and trans-1-bromo-1-
propene produced the desired alkynylbenzaldehyde 4 (86%).
[(-)-Sparteine]2Cu2O2 (8; inset, Scheme 1) mediated oxida-
tive dearomatization9 of 4 afforded vinylogous acid 9 which,
after workup, was directly submitted to Cu(I)-catalyzed
cycloisomerization to afford mitorubrin core structure 3 (58%
yield, two steps, 97% ee).12 The protected orsellinic acid
fragment 10 (Scheme 1) was prepared from commercially
available ethyl 2,4-dihydroxy-6-methylbenzoate via selective
benzylation,13 methylation, and ester hydrolysis.11 Treatment
of 3 with the corresponding acyl chloride derived from 10
using DMAP as the catalyst provided the desired (-)-
mitorubrin precursor 11 (56%). Finally, global deprotection
Figure 2. Retrosynthetic analysis of (-)-mitorubrin and related
azaphilone natural products.
in their side-chain oxidation state may be derived from
mitorubrin, in analogy with their proposed biosyntheses.1c
Azaphilones 1 may be derived from mitorubrin core structure
3 by attachment of an orsellinate fragment. Mitorubrin core
3 may be prepared from alkynylbenzaldehyde 4 using copper-
mediated, enantioselective oxidation followed by cyclo-
isomerization.9 Enyne benzaldehyde 4 may be derived from
the readily available aryl bromide 5.8
Pd(PhCN)2Cl2/PtBu3-mediated Sonogashira coupling10 of
aryl bromide 58 with trimethylsilylacetylene, followed by
(10) (a) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org.
Lett. 2000, 2, 1729. (b) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3,
4295.
(6) (a) Chong, R.; Gray, R. W.; King, R. R.; Whalley, W. B. J. Chem.
Soc., Chem. Commun. 1970, 101. (b) Whalley, W. B.; Chong, R.; Gray, R.
W.; King, R. R. J. Chem. Soc. C 1971, 3571.
(7) Marsini, M. A.; Gowin, K. M.; Pettus, T. R. R. Org. Lett. 2006, 8,
3481.
(8) Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed.
2004, 43, 1239.
(11) See Supporting Information for complete experimental details.
(12) Cycloisomerization of vinylogous acid 9 to azaphilone 3 using our
previously reported conditions (aqueous KH2PO4/K2HPO4 buffer, ref 9) was
found to be ineffective. For CuI/Et3N-mediated cycloisomerization, see:
(a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001,
123, 2074. (b) Kel’in, A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95.
(13) (a) Roush, W. R.; Murphy, M. J. Org. Chem. 1992, 57, 6622. (b)
Hurd, R. N.; Shah, D. H. J. Org. Chem. 1973, 38, 607 (ref 9 therein).
(9) Zhu, J.; Grigoriadis, N. P.; Lee, J. P.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2005, 127, 9342.
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Org. Lett., Vol. 8, No. 22, 2006