Enantioselective phenolic a-oxidation using H2O2 via an unusual double dearomatization mechanism

Article abstract of DOI:10.1021/jacs.8b13006

Feedstock aromatic compounds are compelling low-cost starting points from which molecular complexity can be generated rapidly via oxidative dearomatization. Oxidative dearomatizations commonly rely heavily on hypervalent iodine or heavy metals to provide the requisite thermodynamic driving force for overcoming aromatic stabilization energy. This article describes oxidative dearomatizations of 2- (hydroxymethyl)phenols via their derived bis(dichloroacetates) using hydrogen peroxide as a mild oxidant that intercepts a transient quinone methide. A stereochemical study revealed that the reaction proceeds by a new mechanism relative to other phenol dearomatizations and is complementary to extant methods that rely on hypervalent iodine. Using a new chiral phasetransfer catalyst, the first asymmetric syntheses of 1-oxaspiro[2.5]octa-5,7-dien-4-ones were reported. The synthetic utility of the derived 1-oxaspiro[2.5]octadienones products is demonstrated in a downstream complexity-generating transformation.

Full text of DOI:10.1021/jacs.8b13006

Article
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Enantioselective Phenolic α‑Oxidation Using H2O2 via an Unusual
Double Dearomatization Mechanism
Michael F. McLaughlin,† Elisabetta Massolo,† Shubin Liu,‡ and Jeffrey S. Johnson*,†
†Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
‡Research Computing Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3420, United States
S
* Supporting Information
ABSTRACT: Feedstock aromatic compounds are compelling
low-cost starting points from which molecular complexity can
be generated rapidly via oxidative dearomatization. Oxidative
dearomatizations commonly rely heavily on hypervalent iodine
or heavy metals to provide the requisite thermodynamic
driving force for overcoming aromatic stabilization energy.
This article describes oxidative dearomatizations of 2-
(hydroxymethyl)phenols via their derived bis(dichloroacetates) using hydrogen peroxide as a mild oxidant that intercepts a
transient quinone methide. A stereochemical study revealed that the reaction proceeds by a new mechanism relative to other
phenol dearomatizations and is complementary to extant methods that rely on hypervalent iodine. Using a new chiral phase-
transfer catalyst, the first asymmetric syntheses of 1-oxaspiro[2.5]octa-5,7-dien-4-ones were reported. The synthetic utility of
the derived 1-oxaspiro[2.5]octadienones products is demonstrated in a downstream complexity-generating transformation.
enabling and underexplored intersection between transient
quinone methides and mechanistically validated asymmetric
nucleophilic epoxidations using basic H2O2.9
1. INTRODUCTION
Oxidative dearomatizations of feedstock arenes, including
phenols, are useful in delivering functionalized, complex
organic building blocks.1 These processes often rely on excess,
and in some cases costly, hypervalent iodine or heavy metal-
based (i.e., lead and bismuth) reagents which can give rise to
hazardous byproducts;2 this characteristic may counterbalance
or overshadow the benefit of using inexpensive feedstock
precursors. Reactions using catalytic or heavy metal-free
conditions with benign oxidants, such as oxygen or hydrogen
peroxide, have seldom been explored, especially in asymmetric
fashion.3 Hydrogen peroxide (H2O2) is especially appealing as
an oxidant due to its high efficiency, abundance, and favorable
byproduct profile (i.e., H2O).4
A recent report from these laboratories employed the
Adler−Becker oxidation as the initiating step in a cascade
sequence for the synthesis of highly functionalized hetero-
cycles.5 The Adler−Becker oxidation utilizes stoichiometric
sodium metaperiodate (NaIO4), a hypervalent iodine species,
to convert 2-(hydroxymethyl)phenols 1, also referred to as
salicyl alcohols, into racemic, dearomatized 1-oxaspiro[2.5]-
octa-5,7-dien-4-ones 4 (spiroepoxydienones) (Scheme 1a),6 a
motif which is readily found in a number of biologically active
natural products (Scheme 1c).7 While these oxidation products
have been broadly deployed due to their functionalizable
dienone motif and proclivity to participate in a variety of
cycloaddition reactions,8 the lack of access to enantioenriched
spiroepoxydienones limits their applicability.
ortho-Quinone methides 2 (oQMs) are dearomatized species
that have frequently been employed in forming complex
natural products and synthetically useful building blocks.10
A
strong driving force for rearomatization underlies the high
reactivity of the enone toward [4 + 2]-cycloadditions11 and
1,4-conjugate additions.12 In almost all cases, these trans-
formations irreversibly reset the aromaticity of the resultant
system, limiting further complexity-building transformations.
Reactions involving oQMs resulting in isolable, dearomatized
products are rare.13
Because phenol 1 is formally related to its derived oQM 2 by
dehydration, a key challenge to achieving the title process
would be the identification of conditions that facilitate
dehydrative QM formation under mild conditions: a new
method of QM generation was deemed to be a prerequisite for
success of the project.14 Scheme 1 moreover postulates that
the reaction of a nonstabilized,15 ephemeral QM with H2O2
under basic conditions would initially re-establish aromaticity
affording hydroperoxide 3 but concurrently set the stage for
heterolytic O−O bond cleavage induced by engagement at the
phenolic α-carbon, thereby breaking aromaticity for the second
time in the sequence and creating the spiroepoxide
substructure (4). Employing an asymmetric ion-pairing
phase-transfer catalyst with phenoxide 3 could selectively
facilitate the O−O bond cleavage, affording the enantioen-
riched spiroepoxydienone.
The favorable attributes of the (hydroxymethyl)phenol
dearomatization and the interest in enantioenriched
spiroepoxydienones led to the development of the hypothesis
outlined in Scheme 1b. The reaction design imagines an
Received: December 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b13006
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Article
R1) and expulsion of (−)OR2; the electronic characteristics of
both groups should be critical. To accelerate both steps, the
more electron-deficient mono- and dichloroacetate analogues
were prepared and exhibited drastically improved intermediate
and product yields (entries 3 and 4). Bis(trifluoroacetate) 9
performed at a modest level (entry 5); consequently,
bis(dichloroacetate) analogue 8 was selected for deployment
with additional phenols.17 Dichloroacetate merits some
consideration of the molecular mass “sacrificed”, but the
attractiveness of this acid chloride as a dehydrating agent stems
in no small part from its cheap access on scale, high yields
(>90%), and wide applicability and the fact that bis-
(dichloroacetates) 8 are stable and often exist as easily
handled white solids.
Scheme 1. Oxidative Dearomatization of 2-
(Hydroxymethyl)phenols
Using the optimized racemic conditions identified in Table
1, alkyl-substituted 2-(hydroxymethyl)phenols afforded the
highest yields of the desired spiroepoxide products (Table 2,
Table 2. Racemic Scope of Oxidative Dearomatization
Using Bis(dichloroacetates) of 2-(Hydroxymethyl)phenols
a
2. RESULTS AND DISCUSSION
Considering this hypothesis, we converted primary alcohol
1a16 to its unstable monoacetate 5 in low yield. When phenol 5
was subjected to KOH and H2O2 in MeCN at −5 °C, the
desired spiroepoxydienone 4a was observed (Table 1, entry 1).
Diacetate 6 was prepared in 70% yield and exhibited better
stability than 5. Diacetate 6 in turn gave 4a in somewhat higher
yield relative to the preparation from the monoacetate 5 (entry
2). The efficiency of quinone methide formation could be
affected by the rates of both the phenolic deacylation (loss of
Table 1. Identification of an Optimal Activating Group for
Quinine Methide Formation
a
Reactions performed with 1.0 equiv of 8 and 3.0 equiv of both H2O2
and KOH in MeCN ([8]0 = 0.05 M). Yields refer to isolated yields.
b
c
d
4 equiv of KOH was used. Product isolated as dimer. Slow
e
addition of a solution of 8 and H2O2 over the course of 1 h. 9 equiv
of H2O2 was used. Determined by H NMR spectroscopic analysis.
f
1
4a−c, i−k). Alkyl groups promote the formation of QMs while
reducing the rate of detrimental dimerization processes.18
Electron-withdrawing substituents are reported to inhibit QM
formation18 and lead to oligomerization under basic
conditions;19 however, when using difluorophenol 8e, the
desired product 4e was obtained (47%). In contrast,
difluorophenol 1e failed to provide any discernible product
when NaIO4 was used, highlighting the complementary nature
of this method relative to the Adler−Becker oxidation. Mixed
alkyl and halogen substitution afforded similar yields when 9
a
b
Isolated yield. 1H NMR yield versus internal standard
B
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Article
equiv of peroxide was used (4f). Because benzylic substitution
(R5) often promotes facile rearrangement of spiroepoxydie-
nones to benzodioxoles,5 we used bicyclic substrates 8g−h to
prevent rearrangement and observed good yields with excellent
diastereoselectivity in 4g.
Table 3. Optimization of Enantioselective Oxidative
Dearomatization
a
The substitution pattern around the o-spiroepoxydienone
was a critical determinant of whether the product was isolated
in monomeric or dimeric form.20 Compounds 4i−l with no
substitution at R4 generally favored dimerization upon
isolation. Unsubstituted salicyl alcohol 4l afforded the lowest
yield and resulted in a multitude of side products (i.e.,
oligomers, QM dimers). Substrates prone to dimerization
required that bis(dichloroacetate) 8 and H2O2 were added
over the course of 1 h to reduce excess QM accumulation in
solution. Rapid addition (<1 min) of 8 and H2O2 to the KOH/
MeCN mixture resulted in a 1:1 mixture of the dimer and
chromane 10, the product of trapping of the spiroepoxydie-
none with excess QM in solution (Scheme 2).
a
b
entry
cat.
mol %
[O]
T (°C)
er
yield (%)
1
2
3
4
5
6
7
8
9
CN-1
CN-2
CN-3
CN-3
QN-1
QN-1
QN-1
DHQ-1
QN-2
QN-2
QN-2
20
20
20
20
20
20
20
20
20
20
10
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
UHP
UHP
UHP
UHP
UHP
UHP
UHP
0
0
0
0
0
−10
−20
−10
−10
−40
−40
55:45
50:50
63:37
69:31
85:15
87:13
80:20
87:13
85:13
87:13
87:13
<10
<10
<10
33
50
55
43
52
70
85
10
11
Scheme 2. Observed Competition between Product
Dimerization and Quinone Methide Trapping
UHP
86
a
Reactions were performed using 8a (0.50 mmol), KOH (1.5 mmol),
UHP (1.5 mmol), and [8a]0 = 0.05 M in CH2Cl2. 8a was added over
the course of 2.5 h. er was determined by chiral HPLC. Isolated
yields.
With a mechanistically distinct phenolic oxidation in hand,
we became interested in developing an asymmetric variant of
the title process. Enantioselective transformations utilizing
oQMs lacking methide substitution under basic conditions are
limited due to their high reactivity and propensity to dimerize
rapidly in solution.21 While asymmetric Weitz−Scheffer-type
epoxidations are well established for chalcones and other β-
substituted enones using cinchona alkaloid phase-transfer
catalysts (PTCs), asymmetric epoxidations of enones lacking
β-substitution are rare.22 Employing in situ-generated oQMs
that lack substitution at the methide position presents a
formidable challenge in controlling the stereochemistry of the
resultant spiroepoxide.
Toward this end, we envisioned employing an asymmetric
ion-pairing PTC with phenoxide 3 as a method for controlling
the facial selectivity of heterolytic O−O bond cleavage, a
mechanism closely related to phase-transfer-catalyzed α-
enolate substitution reactions.23 Computational analyses of
these enantioselective reactions have revealed tight catalyst
control of the substrate and electrophile to direct the facial
selectivity of the substitution.24 While PTC α-enolate
substitution reactions frequently involve the coordination of
external electrophiles, more recent examples employ internal
electrophiles using cinchona alkaloid PTCs bearing a free
hydroxyl group.25
b
c
more electron-deficient benzyl groups (i.e., CN-3) improved
selectivity (entry 3). Employing urea·H2O2 (UHP) to limit
water content gave appreciable increases in selectivities and
yields. Switching to quinine as the cinchona alkaloid (QN-1)
greatly improved the er while affording mediocre yields (entry
4). Cooling the reaction temperature to −20 °C resulted in
lower yields and selectivities (entry 5). Dihydroquinine catalyst
DHQ-1 was investigated to minimize potential in situ
derivatization of the catalyst’s olefin via a Diels−Alder
cycloaddition with a transient quinone methide (entry 6).
Disappointingly, this catalyst resulted in the same yields and
selectivities as QN-1. Upon further analysis, increased catalyst
loading resulted in increased side product formation.
Characterization revealed putative oxazonine 11 resulting
from nucleophilic attack on a generated QM by the catalyst’s
quinoline nitrogen followed by cleavage of the quinuclidine
core (Scheme 3). To minimize the nucleophilicity of the
quinoline nitrogen while simultaneously providing steric
hindrance,27 catalyst QN-2 with a trifluoromethyl group was
developed (30% yield over 3 steps from quinine N-oxide),
which considerably improved yields while maintaining
selectivities (entry 7).
We therefore began our catalyst screening by employing
various cinchona alkaloid PTCs with a free hydroxyl group.26
Gratifyingly, phase-transfer catalyst CN-1 with CH2Cl2 solvent
using 30% aqueous H2O2 as the oxidant resulted in a 55:45 er
(Table 3, entry 1). Further catalyst optimization revealed that
Using the optimized catalyst and reaction conditions, various
bis(dichloroacetates) were evaluated for conversion to their
derived enantioenriched epoxides (Table 4). Monomers 4a−d
were all found to afford modest selectivities with high yields;
C
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substrate 4h gave excellent yields but afforded poor selectivity,
although a change in the enantiodetermining step of the
reaction should be noted with these β-substituted substrates.
An evaluation of the reaction mechanism was initiated by
comparing the stereochemical outcome of the H2O2-mediated
oxidative dearomatization of 1g to that when NaIO4 was
employed (Scheme 4a). NaIO4 oxidation proceeded with
Scheme 3. Preventing Catalyst Decomposition
Scheme 4. Mechanistic Insights and Proposed Mechanism
Table 4. Scope of Enantioselective Oxidative
a b c
, ,
Dearomatization
stereoretention (12), while Weitz−Scheffer epoxidation9 of the
planar QM intermediate proceeded with highly diastereose-
lective inversion at the benzylic position (4g). Based upon this
observation, we propose the initial deacylation of the phenolic
dichloroacetate 8a to afford phenoxide A followed by
formation of oQM B via elimination of the benzylic
dichloroacetate. Conjugate addition by hydroperoxide affords
the rearomatized phenoxide C that attacks the hydroperoxide
to give the dearomatized epoxide 4a (Scheme 4b).
The unique and critical role of PTC QN-2 in both QM
generation and stereoselective epoxide formation is evident in
this mechanism. To further understand the catalyst’s role in
promoting the observed stereoselectivity, the transition state of
the epoxidation step between QN-2 and 3a was studied
computationally using density functional theory (DFT)
calculations at the level of M062X28a approximate functional
and a compound Pople basis set.28b,c
Upon analysis of the calculated major stereoisomer (Figure
1a), several important interactions emerge: (a) the hydroxide
nucleofuge is stabilized by two significant hydrogen bonding
interactions derived from the Ar−H on the electron-deficient
(CF3)2Ar ring (H···O distance 2.06 Å) and the benzylic C−H
in close proximity to the ammonium cation (H···O distance
2.16 Å) as well as a weaker hydrogen bonding interaction from
the C−H bond on the bridged quinuclidine (H···O distance
2.67 Å);29 (b) the catalyst −OH group forms a strong
hydrogen bond (H···O distance 1.83 Å) to the phenoxide of
the substrate, orienting the hydroperoxide in close proximity to
a
Reactions were performed using 8 (0.50 mmol), QN-2 (10 mol %),
KOH (1.5 mmol), UHP (1.5 mmol), and [8] = 0.05 M in CH2Cl2, at
b
c
−40 °C. er was determined by chiral HPLC. Values in parentheses
represent recrystallized yields and enantiomeric ratios. 20 mol %
QN-2.
d
however, good to excellent enantioselectivities with good mass
recovery could be achieved via a single recrystallization.
Similarly, dimer 4i exhibited slightly diminished selectivities
that could be upgraded by a single recrystallization, affording
excellent selectivities and modest recovery. It was quickly
apparent that the stability and substitution pattern of the
generated QM were important factors in determining the yield
and enantioselectivities of the reaction. Attempts to access the
enantioenriched unsubstituted dimer 4l resulted in low yields
of the racemic dimer due to rapid QM oligomerization relative
to epoxidation under the basic conditions. In contrast, bicyclic
D
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Scheme 5. One-Pot Enantioselective Oxidative
Dearomatization/Acyl-Nitroso Diels−Alder Cycloaddition
a
b
Isolated as an equilibrating mixture of diasteromers.5 Values in
parentheses represent recrystallized yield, enantiomeric ratio, and
diastereomeric ratio.
further elaborated to afford highly substituted cyclohexanone
rings in a short number of synthetic steps.5
Figure 1. DFT-optimized stereodetermining transition states of QN-2
and 3a.
3. CONCLUSION
We have developed an enantioselective oxidative dearomatiza-
tion of 2-(hydroxymethyl)phenols using H2O2 to afford stable,
dearomatized 1-oxaspiro[2.5]octadienones employing a base-
promoted in situQM activation technique. This reaction
highlights the use of a mild and convenient oxidant to afford
synthetically useful, dearomatized spiroepoxydienones. By
using a new cinchona alkaloid-derived phase-transfer catalyst,
the reaction allows for access to enantioenriched o-spiroepox-
ydienones which were previously inaccessible via the Adler−
Becker oxidation. DFT calculations revealed a highly organized
transition state involving a unique tripartite stabilization of the
hydroxide leaving group leading to the observed facial
selectivity. The synthetic utility of this method for rapid
complexity generation has been demonstrated by preparing an
enantioenriched tricyclic oxazinanone. This chemistry demon-
strates the potential for complementary enantioselective
dearomative processes involving quinone methides, and our
laboratory is currently exploring these possibilities.
the three stabilizing hydrogen bond donors; and (c) the C-2
methyl group on 3a experiences an attractive CH−π
interaction with the quinoline ring (atom to plane distance
of 2.50 Å).30 The apparent synergistic role of the R3N+CH2−
cationic subunits and the (F3C)2Ar−H is to create an
unconventional trifurcated oxyanion hole to stabilize and
accommodate the nascent alkoxide during O−O scission (vide
infra). Such interactions for nucleofuge stabilization have been
previously identified via DFT calculations but arise principally
or solely from the R3N+CH2− cationic subunit.24
We were interested in comparing the stereodetermining
catalyst−substrate interactions leading to the formation of the
minor enantiomer to those leading to major isomer formation.
These interactions were calculated to be similar to the major
isomer (Figure 1b), with the distinction being a ∼90° rotation
of the substrate’s aromatic ring to afford the opposite epoxide
facial selectivity. The transition state leading to minor
enantiomer formation was calculated to be 0.84 kcal/mol
greater in energy than the major enantiomer. This higher
energy transition state can be explained by (a) the loss of the
attractive CH−π interaction between the substrate C-2 methyl
group and the quinoline ring and (b) the observed lengthening
of the hydrogen bonding interaction between the hydroxide
nucleofuge and the benzylic C−H (2.36 Å versus 2.16 Å),
mitigating, in part, the stabilization of the leaving group. The
increased transition state barrier due to the loss of the methyl
CH−π interaction is in accord with experimental evidence
demonstrating reduced enantiocontrol with lack of alkyl
substitution.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b13006.
■
S
CIF file giving data for compound 4i (CIF)
Experimental procedures, characterization, and spectral
data for all new chemical compounds as well as crystal
data and data collection parameters (PDF)
AUTHOR INFORMATION
Corresponding Author
*jsj@unc.edu
■
1-Oxaspiro[2.5]octa-5,7-dien-4-ones (4) are highly reactive
species which readily participate in Michael additions,31
dihydroxylation,31 epoxide openings,32 and cycloadditions.33
To further highlight the synthetic utility of this reaction in
complexity building transformations, enantioenriched spiroe-
poxydienone generation was merged with subsequent base-
promoted acyl-nitroso generation from 1334 to realize a one-
pot oxidative dearomatization/acyl-nitroso Diels−Alder cyclo-
addition. The derived tricyclic oxazinanone 14 (Scheme 5) was
obtained with excellent enantio- and diastereoselectivity after a
single recrystallization. These tricyclic oxazinanones can be
ORCID
Shubin Liu: 0000-0001-9331-0427
Jeffrey S. Johnson: 0000-0001-8882-9881
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The project described was supported by Award R35
GM118055 from the National Institute of General Medical
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Article
̈
(9) Weitz, E.; Scheffer, A. Uber die Einwirkung von alkalischem
Sciences. M.F.M. gratefully acknowledges an NSF Graduate
Research Fellowship. We thank Dr. Brandie Ehrmann (UNC
Mass Spectrometry Core Laboratory) for assistance with mass
spectrometry experiments on instrumentation acquired
through the NSF MRI program under Award CHE-1726291.
We also thank the UNC Research Computing Center for
access to its facilities to perform the DFT calculations.
Professor Marcey Waters (UNC), Dr. Steffen Good (UNC),
and Dr. Samuel Bartlett (UNC) are acknowledged for helpful
discussions. X-ray crystallography was performed by Dr. Blane
Zavesky (UNC).
̈
Wasserstoffsuperoxyd auf ungesattigte Verbindungen. Ber. Dtsch.
Chem. Ges. B 1921, 54, 2327.
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ortho-Quinone Methides in Natural Product Synthesis. Chem. - Eur. J.
2012, 18, 9160. (b) Bai, W.; David, J. G.; Feng, Z.; Weaver, M.; Wu,
K.; Pettus, T. R. R. The Domestication of ortho-Quinone Methides.
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