Selectivity in the Aerobic Dearomatization of Phenols: Total Synthesis of Dehydronornuciferine by Chemo- and Regioselective Oxidation

Article abstract of DOI:10.1002/anie.201710271

We describe a selective aerobic oxidation of meta-biaryl phenols that enables rapid access to functionalized phenanthrenes. Aerobic oxidations attract interest due to their efficiency, but remain underutilized in complex molecule settings due to challenge

Full text of DOI:10.1002/anie.201710271

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Accepted Article
Title: Selectivity in the Aerobic Dearomatization of Phenols:
Total Synthesis of Dehydronornuciferine by Chemo- and
Regioselective Oxidation
Authors: Jean-Philip George Lumb and Kenneth Esguerra
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710271
Angew. Chem. 10.1002/ange.201710271
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Selectivity in the Aerobic Dearomatization of Phenols: Total
Synthesis of Dehydronornuciferine by Chemo- and
Regioselective Oxidation
Kenneth Virgel N. Esguerra,[a] and Jean-Philip Lumb*[a]
Dedication (In memory of Professor Allan Stuart Hay)
Abstract: We describe a selective aerobic oxidation of meta-biaryl
phenols that enables rapid access to functionalized phenanthrenes.
Aerobic oxidations attract interest due to their efficiency, but remain
underutilized in complex molecule settings due to challenges of
selectivity. We discuss these issues in the context of Cu-catalysis, and
highlight the advantages of confining oxygen activation and substrate
oxidation to the catalyst’s inner-coordination sphere. This gives rise to
predictable selectivity that we use for a concise synthesis of the
aporphine dehydronornuciferine.
Issues of selectivity limit aerobic C-H oxidations in complex
molecule settings.[1] Unlike C-H oxidations that use synthetic
oxidants,[2] aerobic oxidations are often limited to relatively simple
substrates, which either contain a single kind of C-H bond or a C-
H bond that is clearly activated for oxidation.[3] This underscores the
unique challenges of working with an oxidant that is prone to
radical-chain mechanisms of oxidation (e.g. autoxidation), has a
four-electron reduction stoichiometry, a triplet electronic structure
and a relatively small steric profile.[4] Metalloenzymes overcome
many of these challenges by confining oxidation to the coordination
sphere of their active sites.[5] This can enable aerobic oxidation of
relatively inert C-H bonds, which remains difficult for synthetic
catalysts.[6],[7],[8] The Type III Cu-enzyme tyrosinase provides a well-
known example, in which a single aromatic C-H bond of tyrosine
Scheme 1. Biosynthetic and biomimetic oxidation of phenols.
(BDE of ~103 kcal/mol) is oxidized in the presence of benzylic (BDE
~ 85 kcal/mol) and heteroatom activated alternatives (BDE ~ 80 –
Cu(II)-semi-quinone radical (SQ) is formed instead of a free ortho-
90 kcal/mol), including the O-H bond of the phenol itself (BDE of
quinone.[13] This important difference has allowed us to sidestep the
~88 kcal/mol) (Scheme 1).[9]
often promiscuous reactivity of ortho-quinones, which frequently
limits their synthetic utility.[14]
Mimicking tyrosinase has been a longstanding goal of industrial
and academic chemists, beginning with early work of Brackman
As part of a general program to improve the utility of O2 in
and Havinga in the 1950s.[10] It is only recently, however, that
synthesis,[7j,15] we became interested in the origin of selectivity for
catalytically active conditions replicating the enzyme’s mechanism
an aerobic oxidation of dihydro-3-phenanthrols that returns 3,4-
phenanthraquinones in high yields (Scheme 2A). Recognizing the
potential value of this oxidation for the synthesis of phenanthrenes
functionalized in the “bay region”,[16] we undertook studies to clarify
its mechanism, scope and synthetic utility. These results form the
basis of our report, which culminates in a selective catalytic aerobic
have emerged.[11] Our group has been particularly interested in a
combination of N,N′-di-tert-butyl ethylene diamine (DBED) and
Cu(CH3CN)4(PF6) (abbreviated CuPF6),[12] which faithfully activates
O2 as the same -2,2-peroxo (P-species) found in the enzyme
(Scheme 1).[13] While this system oxygenates phenols like
tyrosinase, a mechanistic divergence follows atom transfer, and a
C-H oxidation that we use to synthesize the aporphine alkaloid
dehydronornuciferIne (Scheme 1).
At the outset of our studies, we considered two mechanisms for the
[a]
K. V. N. Esguerra, Prof. Dr. J.-P. Lumb
Department of Chemistry
formation of ortho-quinone
2 from dihydro-3-phenanthrol 1
McGill University
801 Sherbrooke St. W., Montreal, Quebec, H3A 0B8 (Canada)
jean-philip.lumb@mcgill.ca
Supporting information for this article is given via a link at the end of
the document.
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Scheme 2. (A) Optimized conditions and control experiments. (B) General mechanistic pathways considered in this work. (C) Control
experiments showing an absence of benzylic C-H oxidation with the DBED/Cu system.
(Scheme 2A), differing in the order of oxidations (Scheme 2B). In
Path A, dehydrogenation at C9-C10 precedes oxygenation at C4 to
afford 3-phenanthrol 3. Oxygenation of polyaromatic phenols
related to 3 with 2-iodoxybenzoic acid (IBX) occurs selectively at
C4,[17] reflecting an energetic bias to preserve aromaticity of the
naphthalene substructure (see Scheme 3a).[18] However, when 3-
phenanthrol 3 was oxidized under our standard conditions, ortho-
quinone 2 was isolated in only 17% yield at complete conversion of
3 (Scheme 1a, entry 1). In the absence of a free phenol at C3
(Scheme 2C), dehydrogenation at C9-C10 is not observed, and the
corresponding dihydrophenanthrenes are re-isolated without loss
of mass balance. Thus, the poor reactivity of 3, and the absence of
C-H oxidation at C9-C10 with the DBED/Cu system lead us to
disfavor Path A.
our previous observations that redox exchange between
catechols and quinones to form semi-quinone radicals can
erode selectivity in the catalytic aerobic oxidation of phenols
and catechols.[14a,14b] This also helps to explain the poor
efficiency of the IBX-mediated oxidation of
1 (Scheme 2A,
entry 2), which must proceed without the stabilizing effects of
a metal complex.
For Path B to be viable, atom transfer must occur selectively
at C4 over C2 in the absence of an obvious electronic bias.
DFT calculations suggest equal spin or charge density at
these two positions in the corresponding phenoxyl or
In Path B, oxygenation at C4 would precede dehydrogenation
at C9-C10 to provide SQ-4 (Scheme 2C). A sequence of
proton transfers via
4 and 5 would afford an increasingly
phenoxide of
2 (see the Supplementary Information), and
electron rich Cu(I)-complex, before a final oxidation to SQ-2
(structure confirmed by x-ray, see the Supplementary
Information). We observe a dose-dependent inhibition of
unlike the relative energies of the regioisomeric 2,3- and 3,4-
phenanthraquinones, the relative energies of the dihydro-
phenanthraquinones (i.e. C9-C10 is saturated) are 1 kcal/mol
in favor of the 2,3-isomer (Scheme 3A). This leads us to
propose a steric bias for oxygenation at C4 that results from
an unfavorable interaction between the C1 phenyl group and
a tert-butyl group of the DBED ligand (i.e. TS1, Scheme
3B).[14d] This interaction would be decreased in TS2, where
the relatively planar bi-aryl bond at C4a would remain
orthogonal to the plane of atom transfer. A similar directing
catalysis when
2 is added at the beginning of the reaction
(Scheme 2a, entries 3-5), suggesting an off-cycle equilibrium
with SQ-2 that must dissociate DBED/Cu(I) prior to re-entering
the catalytic cycle. We also require an increased ratio of 2:1
DBED to CuPF6 relative to our previous work in order to
achieve complete conversion of
panel).[12c] This suggests a pH dependence on the SQ-4
catecholate equilibrium, which should favor at higher
1 (Scheme 2B, lower
/
5
5
effect is observed for the oxidation of isomeric phenol
7
concentrations of DBED. Maintaining Cu-coordination is
important, since control experiments reveal an incompatibility
(Scheme 3C), which returns 1,2-phenanthraquinone in 67%
8
yield by discriminating the twisted biaryl bond at C4 with a
methylene group at C10a. In the absence of a steric bias
(Scheme 3D), oxidation is not selective, and dihydro-3-
of free catechol
also note that catechol
DBED/Cu catalyst (equation 1, bottom). This is consistent with
6
and ortho-quinone
2 (equation 1, top). We
6
is not a viable substrate for the
phenanthrol (9) affords a complex mixture from which coupled
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ortho-, meta- and para-positions with electron donating and
withdrawing groups (entries 1-6 and 14). 1- or 2-Napthyl
substitution is also tolerated (entries 7 and 8), as are
heteroaromatic rings (entries 9 and 10). An isopropyl
substituent at C1 maintains the expected sense of selectivity
for C4, and demonstrates compatability for substrates that
possess an additional benzylic C-H bond at C1 (entry 11).
Sustitution at C9, with either aromatic or aliphatic groups, is
also tolerated, and demonstrates that the efficiency of C9-C10
dehydrogenation is not affected by additional activation of the
C9 hydrogen atom (entries 12 and 13). In the final three
entries, we demonstrate complementary approaches to
angularly fused heteroaromatic ortho-quinones (entries 15-
17) that includes compatability with dehydrogantion across a
-HC-NH- linkage to afford the corresponding angularly fused
isoquinoline-quinone (entry 17).
In addition to their interest as synthetic endpoints,[20] ortho-
quinones generated under our conditions can be used in a range
of 1-pot sequential transformations. This allows us to capitalize on
recent phenol syntheses of the Zhang and Stahl groups[21] to
prepare functionalized phenanthrenes from simple carbonyl
starting materials over a short sequence. Reduction with hydride
or addition of ethane thiol provides differentially substituted 3,4-
dihyroxyphenanthrenes 12 or 13, respectively (Scheme 4B).[12c]
Condensation of an aryl hydrazine or hydrazide occurs at the less
sterically encumbered C-3 carbonyl to provide push-pull azo
phenols 14 or 15.[14c,14e] Related azo switches possess red-shifted
absorbance properties and fast thermal relaxation, which are
attractive for fast information transmission in biologically relevant
contexts.[22] Alternatively, coupling with dihydropyrrole affords N-
aryl pyrrole 16 following condensation and redox isomerization,
whereas the addition of phenyl glycine methyl ester affords
angularly fused benzoxazinone 17 following a similar cascade
terminated by lactonization (structure confirmed by x-ray, see the
Supplementary Information).[14d]
Scheme 3. (A) Relative energies of 2,3- and 3,4-quinones at the
B3LYP/6-31G* level of theory. (B) Schematic representations of
OAT transition states. (C) Phenyl directed C1 oxygenation. (D)
Loss of steric bias.
ortho-quinone 10 and biphenol 11 are isolated in low yields.
The formation of 10 stems from the accessibility of the SQ-
complex, which allows C-O coupling to compete with
tautomerization.[12c,13a] The formation of 11, however, is more
surprising. We have previously demonstrated that the
CuPF6/DBED system favors ortho-oxygenation over radical
As a final illustration of utility, we targeted the aporphine natural
products dehydronornuciferine 20 and its N-methyl derivative 21,[23]
recognizing several features that would probe the limits of the
DBED/Cu(I) system (Scheme 4C). Aporphines are a rich class of
secondary metabolites, endowed with a range of biological
activities.[24] Synthesis of the key dihydrophenanthrols 18 and 19 is
accomplished using Fagnou’s bi-aryl synthesis,[25] (see Supporting
Information). Subsequent regio- and chemoselective oxidation
under our standard conditions highlights compatibility with a
methylene substituent at C1, which does not diminish selectivity for
oxygenation at C4. Dehydrogenation remains selective for C9-C10,
as opposed to the tetrahydro-isoquinoline ring (i.e.
dehydrogenation at C11 and C12). Oxidation of 19 also
coupling,12d and the oxidation of
a product of C-C coupling is observed. Given the absence of
C1 substituent, ortho-oxygenation of may occur
9 is the only instance in which
a
9
competitively at C2 to provide 2,3-phenanthraquinone. To our
knowledge, 2,3-phenanthraquinone is unknown, and the
corresponding 2,3-naphthoquinone is only fleetingly stable.[19]
Our own efforts to prepare or observe 2,3-
phenanthraquinones have been unsuccessful, but we
speculate that their formation during the oxidation of
9 may
lead to radical based C-C coupling. The results in Schemes 2
and 3 lead us to favor Path B as the mechanism of oxidation,
in which steric interactions between the substrate and the
oxidant govern regioselectivity. The results of equation 1 and
Scheme 3C underscore the importance of preserving metal-
coordination throughout substrate oxidation to avoid free
radicals.
With this mechanistic hypothesis in hand, we evaluated the
scope of the reaction (Scheme 4A). Substitution on the key
C1-aryl group is well tolerated. This includes substitution in the
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Scheme 4 (A) Substrate Scope. (B) Diversification of ortho-quinones in a 1-pot, sequential process. (C) Synthesis of dehydronornuciferine.
demonstrates compatibility with a readily oxidizable 3o amine,
leading to the natural products in a concise sequence following
straightforward manipulations.
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[2]
[3]
In summary, we describe a selective aerobic oxidation of phenols,
which enables
a
concise synthesis of functionalized
phenanthrenes. Oxidation reactions play a critically important role
in upgrading feedstock chemicals to endpoints of high value, but
they remain poorly developed when compared to reactions that
employ synthetic oxidants. O2 is an ideal reagent, both in providing
chemical energy to drive bond formation, and an oxygen atom for
C-H oxidation. By confining O2-activation and substrate oxidation
to the inner coordination sphere of a transition metal complex, we
have illustrated a strategy for making aerobic oxidations more
amenable to the synthesis of complex molecules, where issues of
selectivity are paramount.
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Acknowledgements
Financial support was provided by the Natural Sciences and
Engineering Council of Canada (J.-P.L.). We thank Prof. James
Gleason for help with calculations, as well as Dr. Thierry Maris
(University of Montreal) and Dr. Steven Kelley (McGill University)
for help with X-ray crystallography.
[7]
Keywords: aerobic copper catalysis
dehydrogenation • aporphine • quinone
•
phenol oxidation
•
aerobic
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