Photoredox Generated Carbonyl Ylides Enable a Modular Approach to Aryltetralin, Dihydronaphthalene, and Arylnaphthalene Lignans

Article abstract of DOI:10.1021/acs.orglett.0c02286

A one-pot synthesis of dihydronaphthalenes and arylnaphthalenes from epoxides and common dipolarophiles is described. The reaction proceeds through photoredox activation of epoxides to carbonyl ylides, which undergo concerted [3 + 2] dipolar cycloaddition with dipolarophiles to provide tetrahydrofurans or 2,5-dihydrofurans. In the same flask, acid promoted rearrangement affords densely functionalized dihydronaphthalenes and arylnaphthalenes, respectively, in an overall redox-neutral sequence of transformations. Succinct total synthesis (4-6 steps) of pycnanthulignene B and C and justicidin E are reported.

Full text of DOI:10.1021/acs.orglett.0c02286

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Letter
Photoredox Generated Carbonyl Ylides Enable a Modular Approach
to Aryltetralin, Dihydronaphthalene, and Arylnaphthalene Lignans
Edwin Alfonzo, Alexandra M. Millimaci, and Aaron B. Beeler*
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ABSTRACT: A one-pot synthesis of dihydronaphthalenes and arylnaphthalenes from epoxides and common dipolarophiles is
described. The reaction proceeds through photoredox activation of epoxides to carbonyl ylides, which undergo concerted [3 + 2]
dipolar cycloaddition with dipolarophiles to provide tetrahydrofurans or 2,5-dihydrofurans. In the same flask, acid promoted
rearrangement affords densely functionalized dihydronaphthalenes and arylnaphthalenes, respectively, in an overall redox-neutral
sequence of transformations. Succinct total synthesis (4−6 steps) of pycnanthulignene B and C and justicidin E are reported.
been driven by their success and their unnatural congeners as
clinical candidates.2,3 Yet, despite the multitude of chemical
methods that are now available for their assembly, these
frequently fail in their ability to interrogate the structure−
activity relationship (SAR) of the natural products they aim to
access. Therefore, whereas traditional routes to CLs have
focused on target-oriented synthesis, modern approaches have
shifted emphasis toward addressing modularity and diver-
sity.4−13
lassical lignan (CL) natural products, particularly
Caryltetralin, dihydronaphthalene, and arylnaphthalene,
have historically displayed a bevy of promising biological
activities (Scheme 1).1 Synthetic efforts for their synthesis have
Scheme 1. Modular Approach to Aryltetralin,
Dihydronaphthalene, and Arylnaphthalene Lignan
We recently reported a unified approach toward CLs that
leverages tetrahydrofurans (THFs) as a nodal scaffold en route
to all CL subtypes.14 The THFs (1) were derived through [3 +
2] dipolar cycloaddition of photoredox generated carbonyl
ylides and dipolarophiles. We were able to develop a simple,
one-pot protocol that can transform THFs (1) to dihydro-
naphthalenes (2 and 3) through acid-promoted activation of
the THFs to afford intermediate para-quinone-methides
(pQM), followed by an intramolecular Friedel−Crafts
arylation and dehydration. Critical in this sequence’s
progression is the ablation of uncontrolled stereocenters that
arise in the cycloaddition to 1 (2′C and 5′C) and the
emergence of new stereocenters under substrate control. In the
single case investigated, with an unsymmetrical 2,5-diary-
Received: July 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02286
© XXXX American Chemical Society
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Scheme 2. Scope of the Synthesis of Dihydronaphthalenes
from Epoxides and Dimethyl Fumarate
Scheme 3. Scope of the Synthesis of Arylnaphthalenes from
Epoxides and Dimethyl Acetylenedicarboxylate
a
a
a
Epoxide (0.3 mmol, 1 equiv), dipolarophile (3 equiv), DTAC (5 mol
%), PhMe [0.05 M], blue LEDs, then HFIP [0.05 M], HCl (5 equiv),
0−5 °C.
nm, [DTAC*/DTAC•−] = +1.81 V vs SCE) under blue LED
irradiation. The resultant THFs are submitted to 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) and hydrochloric acid (HCl)
under chilled conditions. Temperature control played an
important role in reducing undesired side products and
obtaining high selectivity. Unfortunately, efforts to render the
process catalytic in acid were not successful, likely due to a
surplus of Lewis bases in the THF products, which could
sequester HCl in unproductive equilibria.
a
Epoxide (0.3 mmol, 1 equiv), dipolarophile (3 equiv), DTAC (5 mol
%), PhMe [0.05 M], blue LEDs, then HFIP [0.05 M], HCl (5 equiv),
0−5 °C. Reaction was heated to 40 °C for acid-promoted
rearrangement.
b
ltetrahydrofuran, a mixture of separable regioisomers (2 and 3)
was obtained.
Polyoxygenated dihydronaphthalenes (5-9) were obtained
in good to excellent yields (60−98%) and included examples
of oxygen linkage in the ortho, meta, and para positions.
Importantly, all of these products can be mapped to naturally
occurring lignans.1 Notably, unsymmetrical examples 7 and 8
were obtained with high selectivity despite the possibility of
generating multiple regioisomers. A free phenol 9 was
recovered from the reaction with a benzyl protected epoxide,
albeit with modest selectivity (d.r. 2:1). Of particular interest
for SAR studies were fluorinated dihydronaphthalenes due to
their potential as metabolically more stable unnatural lignans.
In this regard, 10 and 11 with trifluoromethyl and fluorine
substitution were obtained in good yields (50−86%) and
selectivity. Lastly, heterocycles such as indole 12 and furan 13
can participate in this reaction to afford more diverse scaffolds.
Unfortunately, these conditions were unable to activate aryl
groups absent of strongly electron-donating substitution.
Moreover, the lower yields observed in some cases are due
to a dearylation decomposition pathway of the resulting
dihydronaphthalene (8a) into naphthalene (8b), which occurs
under prolonged exposure to the acidic conditions (Scheme
2).17
Given this concise synthesis of dihydronaphthalenes, we
became interested in further expanding the utility of the one-
pot reaction beyond functionality found in naturally occurring
lignans. The integration of unnatural functionality is of
paramount importance given the well-documented metabolic
instability of lignans in vivo, a shortcoming that can be
addressed with more functional group permissive routes.15,16
Here, we demonstrate this approach’s modularity by engaging
a diverse array of epoxides in this sequence of transformations,
demonstrating its potential to accelerate SAR studies of natural
products of interest. Finally, we show that this one-pot
protocol can be leveraged in target-oriented synthesis to access
dihydronaphthalene and arylnaphthalene natural products,
providing a general strategy to all oxidation levels within this
class of molecules from common, readily available precursors.
We began by investigating the scope of the one-pot protocol
on a series of diverse epoxides with dimethyl fumarate
(Scheme 2). In practice, these reactions are conducted on a
preparative scale and involve the cycloaddition of epoxide with
dimethyl fumarate in toluene (PhMe), catalyzed by 2,6-ditert-
butylanthracene-9,10-dicarbonitrile (DTAC, 4) (λmax = 431
B
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a
Scheme 4. Total Synthesis of Pycnanthulignene B and C and Justicidin E
a
Reagents and conditions: Scheme 4A: (1) THT (1.2 equiv), HBF4−OEt2 (1.2 equiv), MeCN [1 M], then MeCN [0.1 M], NaH (4 equiv). (2)
DTAC (5 mol %), CHCl3 [0.2 M], blue LEDs, then HFIP/CHCl3 [0.05 M], 23 → 10 °C, HCl (5 equiv). (3) LiAlH4 (6 equiv), THF [0.05 M], 0
to 23 °C. (4) Pd/C (10 mol %), EtOAc [0.02 M], 23 °C, H2. (5) step 4 in EtOH [0.02 M]. Scheme 4B: (1) LiAlH4 (6 equiv), THF [0.05 M], 0 to
50 °C. (2) Cu(MeCN)4OTf (5 mol %), 2,2′-bpy (5 mol %), TEMPO (2.5 mol %), NMI (10 mol %), 3:2 MeCN/DMF [0.1 M], 23 °C, ambient
air. Scheme 4C: (1) LiAlH4 (6 equiv), THF [0.05 M], 0 °C. (2) BF3−OEt2 (4 equiv), Et3SiH (10 equiv), DCM [0.02 M], −40 to −20 °C. (3)
MsCl (2 equiv), TEA (2 equiv), DCM [0.1 M], 0 to 23 °C. (4) NaI (10 equiv), Zn (3 equiv), DME [0.02 M], Δ. Abbreviations: THT =
tetrahydrothiophene; NaH = sodium hydride; MeCN = acetonitrile; HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol; THF = tetrahydrofuran; EtOAc =
ethyl acetate; 2,2′-bpy = 2,2′-bipyridine; TEMPO = 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl; NMI = 1-methylimidazole; DMF = N,N-
dimethylformamide; MsCl = methanesulfonyl chloride; TEA = triethylamine; DME = 1,2-dimethoxyethane.
Previous work has shown that dihydronaphthalene can be
oxidized to arylnaphthalene, and we wondered whether we
could introduce an additional oxidation level in the cyclo-
addition phase, eliminating the need for external oxidants.18 To
this end, we explored the use of dimethyl acetylenedicarbox-
ylate (DMAD) as a dipolarophile and found that the resulting
2,5-dihydrofurans undergo acid-promoted rearrangement to
arylnaphthalenes (Scheme 3) without the need for further
optimization. To the best of our knowledge, this is the first
example of the rearrangement of 2,5-dihydrofuran to
arylnaphthalene.
which can be found in many neolignans but rarely in CLs.19
Heterocycles like furan 17, thiophene 18, and benzothiophene
19 can participate in this reaction to afford unique, annulated
conjugated systems. Interestingly, a styrene substituted epoxide
readily underwent cycloaddition and rearrangement to provide
20 in modest yield (39%). Lastly, an aryl ether 21 and indole
22 were also obtained in good yields (71−75%) and excellent
selectivity (r.r. > 20:1).
We sought to demonstrate further use of this reaction in
target-oriented synthesis by pursuing lignans with higher
oxidation states such as pycnanthulignene C (23) (Scheme
4a), which showed significant antimicrobial activity against a
panel of drug-resistant pathogens.20 Starting from commer-
cially available benzyl alcohol 24, we generated sulfonium ylide
25 and engaged aldehyde 26 in a one-pot Johnson−Corey−
Arynaphthalenes 14 and 15, which can be readily mapped to
known natural products, were obtained in excellent yields
(89−95%) and selectivity (r.r. > 20:1). Another interesting
functionality is 1,4-benzodioxane present in compound 16,
C
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Chaykovsky reaction.21 This afforded epoxide 27 in 98% yield
and d.r. 5:1, which was used as a mixture for the photoredox
catalyzed [3 + 2] dipolar cycloaddition. On a gram scale, we
found that cycloaddition in chloroform (CHCl3) followed by
dilution with HFIP and HCl addition at 10 °C proved
sufficient to elicit the formation of 28 without the need of a
solvent exchange (95%, r.r. > 20:1). At higher temperatures, a
second regioisomer at C5 was observed (r.r. 4:1). LiAlH4
reduction and hydrogenation (Pd/C) in ethyl acetate (EtOAc)
of the resulting diols produced pycnanthulignene C (23) in
four steps and 88% overall yield. Interestingly, in the presence
of ethanol (EtOH), it was found that the diol was
quantitatively reduced by 3 equiv of H2 to afford 29.
Justicidin E (30), another arylnaphthalene lignan, was easily
accessed with similar efficiency (Scheme 4b).22 In this
example, 14 was reduced with LiAlH4 under elevated
temperatures to afford diol 31 in 85% yield. 31 was reoxidized
regioselectively at the sterically more accessible primary
alcohol using Stahl’s protocol for lactonization.23 This
provided justicidin E (30) in an overall 68% yield and four
steps.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02286.
■
sı
General information, experimental procedures, and
characterization data for all new compounds (PDF)
FAIR data, including the primary NMR FID files, for
compounds 5−23, 28−32, 34, S8, S9, S11−S13, and
S15−S17 (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
Aaron B. Beeler − Department of Chemistry, Boston University,
Boston, Massachusetts 02215, United States; orcid.org/
0000-0002-2447-0651; Email: beelera@bu.edu
Authors
Edwin Alfonzo − Department of Chemistry, Boston University,
Boston, Massachusetts 02215, United States
Alexandra M. Millimaci − Department of Chemistry, Boston
University, Boston, Massachusetts 02215, United States
Lastly, we targeted a dihydronaphthalene, pycnanthulignene
B (32) (Scheme 4c).20 Reduction of 2 with LiAlH4 afforded
33 as a single isomer after chromatography. Our original
approach to 32 involved in situ global mesylation followed by
LiAlH4 reduction of 33. Unfortunately, that strategy was
complicated by competing reductive olefin transposition of the
allylic mesyl group and demesylation of the primary mesylate,
affording low yields.24 Efforts to remedy this with 2-
propanesulfonate, which is known to be stubborn to reduction
at sulfur, were promising. However, the desired product was
often isolated with inseparable and unidentifiable byprod-
ucts.25 A revised approach that involved stepwise deoxygena-
tion was undertaken in hopes of solving mass balance issues.
Inspired by the enzymatic reduction of coniferyl alcohol to
isoeugenol with NADPH, a monomeric precursor to lignans,
we engaged 33 in a series of chemical allylic reductions.26 After
some experimentation, it was found that upon treatment with
BF3−OEt2 at −40 °C, activation to a presumed extended, exo-
cyclic pQM occurs. Et3SiH was added dropwise, and the
reaction was allowed to warm to −20 °C. A 1 h stir period was
followed with quenching at the same temperature. After
workup, 34 was obtained in 97% yield with no chromatog-
raphy necessary. The developed allylic reduction is of note and
may serve as a useful reaction in the differentiation of other
lignan skeletons to access natural products of interest.
Removal of the primary alcohol in 34 required a change in
mechanism to combat selectivity issues encountered under a
two-electron paradigm. We found that an in situ Finkelstein
reaction with NaI and single electron transfer (SET) reduction
with Zn ofmesylated 34 delivered pycnanthulignene B (32) in
73% yield, devoided of the byproducts that plagued other
routes.27
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02286
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial Support from the National Science Foundation (ABB
CHE-1555300) is gratefully acknowledged. We thank Dr.
Norman Lee (Boston University) for high-resolution mass
spectrometry data and analyses. NMR (CHE-0619339) and
MS (CHE-0443618) facilities at Boston University are
supported by the NSF.
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