Synthesis of the azaphilones using copper-mediated enantioselective oxidative dearomatization

Article abstract of DOI:10.1021/ja052049g

An approach to the asymmetric synthesis of the azaphilone natural products is reported involving copper-mediated enantioselective oxidative dearomatization of o-alkynylbenzaldehydes. The approach was successfully applied to the synthesis of (-)-S-15183a a

Full text of DOI:10.1021/ja052049g

Published on Web 06/10/2005
Synthesis of the Azaphilones Using Copper-Mediated Enantioselective
Oxidative Dearomatization
Jianglong Zhu, Nicholas P. Grigoriadis, Jonathan P. Lee, and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment, Boston UniVersity,
Boston, Massachusetts 02215
Received March 31, 2005; E-mail: porco@chem.bu.edu
The azaphilones are a structurally diverse family of natural
products containing a highly oxygenated bicyclic core and chiral
quaternary center (cf. S-15183a,1 1, Figure 1). We recently reported
the synthesis of (()-1 and several unnatural azaphilones employing
gold(III)-catalyzed cycloisomerization of o-alkynylbenzaldehydes
to 2-benzopyrylium salts and subsequent I(V)-mediated oxidation.2
In addition to our studies, a number of synthetic efforts have been
reported toward the racemic synthesis of the azaphilones3 with only
Figure 2. Proposed Mechanism for Formation of 4/4′.
Table 1. Development of Copper-Mediated Asymmetric Oxidation
a single report regarding asymmetric control of the quaternary
center.4 Herein, we disclose an enantioselective approach to the
azaphilones employing copper-mediated asymmetric oxidation5 of
phenolic substrates.
entry
ligand
solvent
temp (
°
C)
conv. (%)a
ee (%)
1
2
14
18
18
18
18
18
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-78
-78
-40
-40
-20
-40
44
50
38
24
27
35
11b
51
66
20
59
81
Figure 1. Retrosynthetic Analysis.
3
4c
5
Our initial approach is outlined in Figure 1. Our previous studies
indicated that (()-2 could be obtained by oxidation of 2-benzo-
pyrylium salt 3 (Figure 1, inset) using o-iodoxybenzoic acid (IBX)
and Bu4NI as catalyst.2 However, thus far our efforts to achieve
asymmetric oxidation of 3 to 2 have not been successful. Since
previous synthetic3a and biosynthetic studies6 have demonstrated
that pyronoquinones such as 4 may be viable precursors to the
azaphilones, we shifted our focus to biomimetic asymmetric
oxidation7 of the pyronoquinone 4 derived from o-alkynylbenz-
aldehyde 5.
We first evaluated the feasibility of preparing 4 as a substrate
for asymmetric oxidation. After NMR experiments indicating that
2-benzopyrylium salt 3 could be deprotonated to afford pyrono-
quinone 4 with diisopropylethylamine (DIEA), we recognized that
it should be possible to prepare pyronoquinone 4 directly via
cycloisomerization of alkynylbenzaldehyde 5 (Scheme 1). Treatment
of 5 with 5 mol % Au(OAc)32,8 in anhydrous CDCl3 (50 °C) led to
formation of pyronoquinone 4 as the major tautomer, which was
6
toluene/CH2Cl2 (1:1)
a Conversion was determined by 1H NMR analysis of 2 and the keto
aldehyde 6 (from hydrolysis of pyronoquinone 4). b Ligand 14 slightly
favored the S-enantiomer of 2. c No DIEA was added.
confirmed by HMBC analysis.9 Pyronoquinone 4 was found to be
unstable and readily hydrolyzed to keto aldehyde 6. Methyl ether
7 also smoothly underwent cycloisomerization to produce pyrono-
quinone 8, while regioisomer 9 failed to undergo cycloisomerization.
A generalized mechanism (Figure 2) involves activation of o-
alkynylbenzaldehyde 5 by Au(III) to afford metal ate complex 10,2
which may be converted to zwitterion 11 after proton transfer from
the C6 hydroxyl to C4. Intermediate 11 may afford the pyrono-
quinone 4/4′ after subsequent bond rearrangement.
Regarding biomimetic oxidation, our initial question centered
on whether tyrosinase “mimics”10 based on Cu/O2 enzymes could
mediate oxo transfer to the “tyrosine-like” pyronoquinone 4.
Recently, Stack has employed readily available bidentate, nitrogen
ligands to prepare such Cu/O2 oxidant systems.10a,b Two examples
shown in Table 1 include binuclear copper-oxo (O, bis-µ-oxodi-
copper(III)) complex 12 and the copper-peroxo (P, µ-η2:η2-
peroxodicopper(II)) complex 13. In initial experiments, we found
that both 12 and 13 (X ) PF6-) oxidized pyronoquinone 4 to 2
(-78 °C, CH2Cl2). We also observed that oxidation reactions were
cleaner with added DIEA. This result encouraged us to investigate
asymmetric oxidation of pyronoquinone 4 employing chiral, non-
Scheme 1. Preparation of a Pyronoquinone Substrate
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C O M M U N I C A T I O N S
and intramolecular amine addition (entry 5).9 When o-alkynyl-
benzaldehydes derived from propargylic ethers were subjected to
copper-mediated oxidation, severe side reactions were detected,
likely due to the active propargylic functionality. An alkynyl-imine
from condensation of 5 and butylamine was also investigated in
the copper-mediated oxidation and in initial studies showed low
enantioselectivity.
In conclusion, we have developed a highly enantioselective
approach for the biomimetic synthesis of the azaphilones involving
copper-mediated enantioselective oxidative dearomatization of
o-alkynylbenzaldehydes. Further studies, including asymmetric
oxidative dearomatization of other substrates, are currently in
progress and will be reported in due course.
Scheme 2. Copper-Mediated Enantioselective Oxidative
Dearomatizationa
a Conditions: (a) 2.2 equiv of Cu(CH3CN)4PF6, 2.4 equiv of (-)-
sparteine, DIEA, DMAP, O2, CH2Cl2, -78 to -10 °C; (b) aq. KH2PO4/
K2HPO4 buffer (pH 7.2), CH3CN, room temperature, 98% ee, 84% yield,
two steps.
Table 2. Enantioselective Synthesis of Diverse Azaphilonesa
Acknowledgment. We thank Prof. Olga Gursky (Boston
University School of Medicine) for assistance with CD spectra,
Mr. Gerard Rowe for help with the low temperature UV/vis, and
Profs. Sean J. Elliott and John P. Caradonna (Boston University)
for helpful discussions. We thank Bristol-Myers Squibb for research
support (Unrestricted Grant in Synthetic Organic Chemistry to
J.A.P, Jr.).
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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racemic diamine ligands (Table 1). Use of pybox 14 resulted in
11% ee at -78 °C (entry 1). Ligands 15, 16,11 and 17 did not afford
any conversion. We were pleased to discover that the Cu2L2O2
complex generated from Cu(CH3CN)4PF6 and (-)-sparteine (18)9,12
reacted cleanly with pyronoquinone 4 and produced azaphilone 2
in 51% ee (entry 2). Further optimization afforded 2 with 81% ee
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Due to the instability of pyronoquinone 4, we investigated
o-alkynylbenzaldehyde 5 as an oxidation substrate. To our delight,
Cu2[(-)-sparteine]2O2-mediated enantioselective oxidative de-
aromatization13 of 5 afforded the corresponding vinylogous acid
19 (Scheme 2).14 However, only up to 60% conversion was obtained
when 1.6 equiv of Cu2[(-)-sparteine]2O2 was employed. Further
optimization studies identified 4-(dimethylamino)pyridine (DMAP)
as an effective additive15 to promote full conversion to vinylogous
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duced in 98% ee (84% yield, two steps). Use of Cu(CH3CN)4OTf
as a Cu(I) source reduced the ee only slightly (92%). Following
our previously reported procedure,2 we prepared (-)-1,9 which was
confirmed to be R by CD spectroscopy,17 thereby assigning the
absolute configuration of (-)-S-15183a.
The copper-mediated asymmetric oxidation-cycloisomerization
sequence was found to be compatible with o-alkynylbenzaldehydes
20 and 21 containing an enyne and an aromatic functionality, as
well as 22 and 23 bearing a benzyl ether and an ester substituent
to afford the corresponding azaphilones 24-27, respectively (entries
1-4, Table 2). In addition, o-alkynylbenzaldehyde 28 featuring a
terminal NH-Boc substituent was also well-tolerated in this
methodology to produce the desired azaphilone, which was further
converted to tricyclic amino-azaphilone 29 after Boc deprotection
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