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org/OrgLett Letter

Total Synthesis of (S)‑Cularine via Nucleophilic Substitution on a

Catechol
Zheng Huang, Xiang Ji, and Jean-Philip Lumb*
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ABSTRACT: Catechols are part of many essential chemicals and are valuable, typically nucleophilic intermediates used in synthesis.
Here we describe an unexpected transformation in which they play the role of the electrophile in a formal nucleophilic aromatic
substitution. We made this discovery while studying a seven-membered dioxepin ring formation during a synthesis of the
benzyltetrahydroisoquinoline (S)-cularine. We suggest a chain mechanism for this new transformation that is triggered by molecular
oxygen and that propagates an electrophilic ortho-quinone.

C atechols are redox-active, electron rich aromatic rings

that are commonly found in natural products,
pharmaceuticals and naturally occurring materials.1 They are
also important intermediates in organic synthesis that are
most frequently used as nucleophiles in redox neutral
substitution reactions. In biology and materials science, the
redox lability of catechols is often an asset.2 In synthetic
chemistry, however, it is typically a hindrance that requires
care to exclude molecular oxygen (O2).3 In its presence,
catechols (CAT in Scheme 1A) undergo facile 1e− | 1H+
oxidation to the semiquinone radical (SQ),4 which can
polymerize or disproportionate. CATs and ortho-quinones
(OQs) can themselves exchange oxidation states through a
reversible 2e− | 2H+ redox couple5 that typically favors the
OQ with more electron-donating substituents and the CAT
with more electron-withdrawing substituents.6 Spontaneous
aerobic oxidation (autoxidation) is rarely clean,7 and as a
consequence, CATs are most frequently masked throughout a
synthesis or installed in its late stages.
In this work, we present an interesting case where the
autoxidation of a catechol is well-behaved and gives rise to a
challenging seven-membered ring formation by a net-redox
neutral nucleophilic aromatic substitution (SNAr). We made
this discovery while investigating the natural product (S)-
cularine (1)8 and its biosynthesis from crassifoline (2) by
oxidative cyclization.9,10 Whereas we were initially interested
in mimicking this process using copper (Cu) catalysis,11 we
ultimately discovered a metal-free and redox-neutral cycliza-
tion of substituted catechol 3 in the presence of air and
tetrabutylammonium fluoride (TBAF) (Path B, Scheme 1B).
In addition to its unique mechanism,12,13 the mild nature of
these reaction conditions caught our attention. Diaryl ethers
are part of many biologically active small molecules, and their
synthesis remains a topic of great interest.14 Herein we
present this discovery and show how it could expand the
currently available toolbox of catechol-based transformations.
Applying our C−O coupling logic to the retrosynthetic
simplification of 1 led us to identify phenol 5 as a strategic
target for the synthesis (Scheme 2A).11 In its own right, 5
presents a challenge of needing to install the 7,8-disubstituted
1-benzyl-1,2,3,4-tetrahydroisoquinoline (abbreviated as
BnTHIQ) while tolerating differentially protected phenols
Received: December 2, 2020
Published: December 16, 2020

© 2020 American Chemical Society https://dx.doi.org/10.1021/acs.orglett.0c04000

236 Org. Lett. 2021, 23, 236−241
Organic Letters pubs.acs.org/OrgLett
Scheme 1. (A) Reversible Redox Exchange That Relates
Catechol, the Semiquinone Radical, and ortho-Quinone
and (B) Our Initially Proposed Oxidative Cyclization for
the Construction of the Seven-Membered Diaryl Ether in
(S)-Cularine and the Final Approach with the Discovery of
a Formal SNAr on Catechols
at C4′ and C8.15 A substituent at C8 precludes the most
common syntheses based on Pictet−Spengler or Bischler−
Napieralski cyclizations to form the C1−C8a bond. There-
fore, we devised an alternative that capitalized on Ellman’s
chiral sulfonamide technology16 to install the lone chiral
center at C1 and our recently reported modification of the
Pomeranz−Fritsch cyclization17 to install the isoquinoline
ring by forming the C4−C4a bond.
Our forward synthesis began by the titanium-mediated
condensation of (R)-tert-butylsulfinamide (9) with the TBS-
silyl ether of ortho-vanillin 12 to provide (R)-tert-butylsulfinyl
imine 13 (Scheme 2B).18 A diastereoselective addition of
Grignard reagent 8 via closed TS-I19 delivered sulfinyl amine
14 in 87% yield with >20:1 dr on a 9 g scale. Ellman’s
auxiliary was then removed to allow reductive alkylation with
a glyoxal dimethyl acetal (11) before tosyl protection of the
amine provided 7 with >99% ee and in 83% yield on a scale
of 7−9 g.20 To effect the desired Pomeranz−Fritsch
cyclization, we employed our recently reported conditions,17
consisting of 3 equiv of TMS-OTf and 4 equiv of 2,6-lutidine.
We were pleased to find that the cyclization of 7 to 15
proceeded in 83% yield on a 14 g scale without erosion of
the ee.21 Subsequent hydrogenation with Pd/C removed the
benzyl-protecting group and reduced the C3−C4 double
bond to complete the synthesis of phenol 5 in a longest
linear sequence (LLS) of seven steps. Beginning from o-
vanillin, it proceeded in 42% overall yield on a multigram
scale and highlights a concise and stereoselective synthesis of
C8-substituted BnTHIQs.22
237
Letter
With 5 in hand, we attempted several conditions for its
direct oxidative cyclization based on our previous work,11 but
unfortunately, all attempts led to intractable mixtures without
any evidence of cyclization. Consequently, we turned our
attention to an intermolecular coupling between silyl-
protected OQ 16 and 4-nitrophenol (17), with the idea of
closing the seven-membered ring via a redox neutral
substitution (Scheme 3).23 Gratifyingly, the catalytic aerobic
coupling of 16 and 17 using CuCl (10 mol %) and N,N′-di-
tert-butyl-ethylenediamine (DBED) (10 mol %) afforded
catechol 3 in 88% yield on a 3 g scale, following a reductive
workup using Na2S2O4.24 Given the well-known challenges of
forming diaryl ethers in complex settings,14 the yield of this
coupling and its completion within 1 h at room temperature
using inexpensive and commercially available reagents is
noteworthy.
Whereas we had initially intended to simply remove the
silyl ether in 3, we were surprised to find that the use of
TBAF in the presence of air afforded dibenzodioxepin 4 in
what appeared to be a redox-neutral substitution. Because 4
was somewhat unstable, we immediately advanced the crude
material by methylation to the corresponding dimethyl ether
(not shown). Under our optimized conditions, this two-step
sequence provided the product in 62% yield; notably, the
cyclization could be run on a gram scale. This led to the
synthesis of (S)-cularine (1) in two straightforward steps,
completing a LLS of 14 steps that proceeded in 15% overall
yield.
Given the redox lability of CATs, the unusually clean
cyclization of 3 caught our attention, and whereas a more in-
depth mechanistic study is ongoing, a series of optimization
studies (Table 1) support our preliminary mechanistic
hypothesis (Scheme 4). The cyclization is redox-neutral and
produces 4-nitrophenol (17) as a byproduct that we can
recover in good yield (Table 1, entry 1).25 At shorter
reaction times, we observe the product along with uncyclized
phenol (±)-18 (entry 2); likewise, we see decreased amounts
of cyclized product (±)-4 and increased amounts of phenol
(±)-18 if the reaction is run under an atmosphere of N2
(entry 3) or buffered with acetic acid (entry 4).26 These
results are consistent with a rapid desilylation of 3 to produce
18, followed by a relatively slow autoxidation of the CAT to
OQ 19 that would be accelerated at an increasing pH
(Scheme 4A,B).4,27,28 Once formed, 19 would establish an
equilibrium with 20 by forming the seven-membered ring,
consistent with previous nucleophilic substitutions on β-
substituted OQs.23 But to produce CAT 4, OQ 20 must
undergo a 2e− | 2H+ redox exchange with CAT 18 that was
initially surprising because it appeared to place the more
electron-rich, methoxy-substituted diaryl ether at C6′ of 4
and the more electron-withdrawing nitro-substituted diaryl
ether at C6′ of 19. However, a careful inspection of OQ 20
revealed a puckered conformation of the seven-membered
oxepin29 that prevents the delocalization of the oxygen lone
pair into the quinone π-system (Scheme 4C). Consequently,
the β-phenoxy substituent, which begins as an electron-
donating group in starting material 18, ends as an inductively
withdrawing group that makes OQ 20 a stronger oxidant
than OQ 19. By analogy, CAT 4, possessing the more
electron-withdrawing oxygen atom at C6′, is thermodynami-
cally favored, creating a driving force for conversion to the
product and propagation of the chain.3,30
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Scheme 2. (A) Retrosynthetic Analysis of the Isoquinoline Core and (B) Synthesis of the Key Tetrahydroisoquinoline
Intermediatea

a
Reagents and conditions: (a) (R)-tert-butylsulfinamide (1.2 equiv), Ti(OEt) 4 (2.0 equiv), THF, rt, overnight, 93%. (b) 4-
Benzyloxybenzylmagnesium chloride (2.0 equiv), CH2Cl2 (0.1 M), −48 °C, 4 h, then rt, 12 h, 87%, >20:1 dr. (c) HCl (2.0 equiv), MeOH, 0
°C, 10 min, then NEt3 (4.0 equiv), glyoxal dimethyl acetal (1.5 equiv), rt, overnight, then NaBH4 (3.0 equiv), 0 °C − rt, 1 h, 95%. (d) TsCl (4.0
equiv), DMAP (20 mol %), NEt3 (10.0 equiv), CH2Cl2, rt, 36 h, 87%. (e) TMSOTf (3.0 equiv), 2,6-lutidine (4.0 equiv), CH2Cl2, 0 °C − rt, 4 h,
83%. (f) 10 wt % Pd/C (20 wt %), H2 (10 psi), MeOH/EtOAc, 88%.

Scheme 3. Completing the Total Synthesis of (S)-Cularine via an Unexpected Redox-Neutral Substitution on Catechola

a
Reagents and conditions: (a) IBX (1.2 equiv), DMF, rt, 3 h, then aq. Na2S2O4, 82%. (b) NaIO4 (1.2 equiv), CH2Cl2/H2O, rt, 1 h. (c) CuCl (10
mol %), DBED (10 mol %), 4-nitrophenol (1.2 equiv), O2 (1 atm), CH2Cl2, rt, 1 h, then aq. Na2S2O4, 88% over two steps. (d) TBAF·3 H2O (2.0
equiv), THF, rt, 18 h, air. (e) MeI (5.0 equiv), Cs2CO3 (5.0 equiv), DMSO, rt, 12 h, 62% over two steps. (f) Lithium naphthalenide (4.0 equiv),
−78 °C, 2 h, 90%. (g) HCHO (2.0 equiv), rt, 4 h, then NaBH4 (5.0 equiv), 0 °C − rt, 1 h, 81%.

238 https://dx.doi.org/10.1021/acs.orglett.0c04000
Org. Lett. 2021, 23, 236−241
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Table 1. Screening of Conditions for the Cyclization of the Racemic Catechol Precursora

yield (%)b
entry atmosphere additive time (h) (±)-18 (±)-4
1c air 20 <5 71
2 air 4 20 62
3 N2d 20 57 43
4 air HOAc (5 equiv) 20 55 45
5e air HOAc (5 equiv) 20 34 56
a
Reaction performed on a 0.05 mmol scale. bYield determined by 1H NMR using hexamethylbenzene as the internal standard. c4-nitrophenol was
recovered as its methyl ether after the methylation step. dReaction performed under a balloon of N2. eReaction performed at 50 °C.

Scheme 4. (A) Mechanistic Hypothesis for the Seven-Membered Ring Formation via Formal SNAr on Catechol, (B)
Autoxidation of Catechol 18 to ortho-Quinone 19, and (C) Conformational Analysis of the Proposed Acyclic and Cyclic
ortho-Quinone Intermediates

In summary, we have shown that the redox lability of

CATs need not be an impediment to reaction design and
■ ASSOCIATED CONTENT

that in fact, the transient nature of intermediate OQs can *

sı Supporting Information

enable challenging bond formation under relatively mild

conditions. Catechols and phenols are present in many
natural products and pharmaceuticals,1b,31 and they are also
building blocks that are increasingly available from renewable
sources of carbon.32 Their increased utilization across these
stages of the chemical value chain could have many beneficial
impacts, including the valorization of emergent chemical
feedstocks and the diversification of existing biologically
active scaffolds.
239
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04000.
Experimental procedures, characterization data, and
copies of NMR spectra for all synthetic intermediates-
(PDF)
https://dx.doi.org/10.1021/acs.orglett.0c04000
Org. Lett. 2021, 23, 236−241
Organic Letters
■
pubs.acs.org/OrgLett
AUTHOR INFORMATION
Corresponding Author
Jean-Philip Lumb − Department of Chemistry, McGill
University, Montreal, Quebec H3A 0B8, Canada;
orcid.org/0000-0002-9283-1199; Email: jean-
philip.lumb@mcgill.ca
Authors
Zheng Huang − Department of Chemistry, McGill
University, Montreal, Quebec H3A 0B8, Canada
Xiang Ji − Department of Chemistry, McGill University,
Montreal, Quebec H3A 0B8, Canada
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04000
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Financial support was provided by the Natural Sciences and
Engineering Council (NSERC) of Canada (Discovery Grant
to J.-P.L.), the Fonds de Recherche du Québec Nature et
Technologies (FRQNT) (Team Grant to J.-P.L.), and the
FRQNT Center for Green Chemistry and Catalysis.
■
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