Total Synthesis of (S, S)-Tetramethylmagnolamine via Aerobic Desymmetrization

Article abstract of DOI:10.1021/acs.orglett.9b03559

We describe a concise synthesis of the pseudodimeric tetrahydroisoqunoline alkaloid (S,S)-tetramethylmagnolamine by a catalytic aerobic desymmetrization of phenols. Desymmetrization reactions increase molecular complexity with high levels of efficiency, b

Full text of DOI:10.1021/acs.orglett.9b03559

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Total Synthesis of (S,S)‑Tetramethylmagnolamine via Aerobic
Desymmetrization
†
Zheng Huang, Xiang Ji, and Jean-Philip Lumb*
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
*
S Supporting Information
ABSTRACT: We describe a concise synthesis of the pseudo-
dimeric tetrahydroisoqunoline alkaloid (S,S)-tetramethylmag-
nolamine by a catalytic aerobic desymmetrization of phenols.
Desymmetrization reactions increase molecular complexity with
high levels of efficiency, but those that do so by aerobic oxida-
tion are uncommon. Our conditions employ molecular oxygen
as an oxygen atom transfer agent and a formal acceptor of
hydrogen, enabling two mechanistically distinct aromatic C−H
oxygenation reactions with high degrees of selectivity.
olecular oxygen (O ) is an attractive reagent for chemi-
cal synthesis (Scheme 1A). It is renewable and non-
ortho-quinone (Q1) following (step 4) protonation of the hydrox-
ide bridge and (step 5a) redox between the ligand and the metal
centers, the synthetic system releases a Cu(II)-semiquinone
radical complex (SQ) (step 5b). The ensuing oxidative C−O
coupling with the starting phenol is rate determining (step 6)
and provides the corresponding substituted ortho-quinone
product (Q2) while releasing DBED-Cu(I) to close the
2
1
M
toxic, and its reduction to water (H O) provides a strong ther-
2
modynamic driving force that can offset otherwise challenging
bond forming reactions. Despite these advantages, O can be
2
difficult to use when oxidizing C−H bonds in complex mole-
cules, where issues of chemo- and regioselectivity outweigh
2
12
synthetic efficiency. O has a small steric profile, a noncanonical
2
catalytic cycle. O serves multiple roles over the course of
2
−
+
3
4
e |4 H redox stoichiometry, and a triplet electronic structure.
These factors often lead to radical chain processes that can be
this reaction. The first is as a reagent for OAT that reduces
the C symmetry of the phenol to the C symmetry of either
2v
s
difficult to control when potential sites of oxidation are not
quinone (enzymatic) or SQ (biomimetic system). This dis-
tinction is important as the retention of Cu in the SQ forces
the biomimetic system to engage another equivalent of the
starting phenol in a C−O coupling. This step is distinct from
the first OAT and ensures that the starting material is con-
sumed in two distinct processes over the course of the reaction.
C−O bond formation is driven by the favorable reduction
4
electronically differentiated.
To overcome these challenges, our group has adopted a
bioinspired strategy of utilizing O that is inspired by metallo-
2
5
,6
enzymes (Scheme 1A). By coordinating O to transition
2
metals within their active sites, metalloenzymes can exert con-
trol over aerobic oxidations by defining the coordination envi-
1a,b,7
ronment surrounding the metal center.
Our group has
of 1/2 O , highlighting its second role as a formal acceptor
2
been particularly interested in the type III Cu enzyme
tyrosinase (Scheme 1B), which catalyzes the aerobic oxygen-
ation of L-tyrosine in the first and rate-limiting step of melano-
of H2.
Herein, we describe the application of this catalytic aerobic
process to the synthesis of the pseudosymmetric tetrahy-
droisoquinoline (THIQ) alkaloid (S,S)-tetramethylmagnol-
amine (1) (Scheme 2A). 1 is a member of the diaryl ether
subfamily of THIQs, which encompass a number of structur-
8
genesis (not shown). Building upon bioinorganic studies of
9
,10
Stack and others,
our group showed that the enzyme’s
mechanism of O activation and oxygen atom transfer (OAT)
2
could be recreated by a simple and commercially available
catalytic system, composed of Cu(CH CN) (PF ) (abbreviated
13
ally unique and biologically active members. Among them
3
4
6
1
1
are the well-known macrocyclic diaryl ether tubocurarine
CuPF ) and N,N′-di-tert-butylethylenediamine (DBED).
6
14
(
4), which is a potent muscle relaxant, and the chemo-
When applied to the oxidation of simple para-substituted
phenols, this system catalyzes ortho-C−H oxygenation through
a series of discrete steps consisting of the following: (step 1)
15
therapeutic (S,S)-thalicarpine (3). The family members share
defining diaryl ethers, typically linking two electron-rich aro-
matic rings. They also possess two basic amine functionalities
separated by ∼14 Å, which are believed to be protonated at
physiological pH. This has become a defining structural
2
2
activation of O as its di-Cu(II) μ-η ,η peroxo complex (P),
2
(
step 2) coordination of a phenolate, and (step 3) electrophilic
aromatic substitution onto the Cu O core. Although these
2
2
discrete steps replicate those of the enzyme, the fate of the
ensuing bridged di-Cu(II)-catecholate (Cu -Cat) differs
Received: October 8, 2019
2
between the two systems. Whereas tyrosinase releases a free
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. (A) Bioinspired Strategies for the Utilization of
O and (B) Biomimetic Aerobic Oxidation of Phenol
2
temperatures makes them capricious in complex molecule
settings. This includes the formation of the diaryl ether in
19
(
S,S)-tetramethylmagnolamine (1), which was synthesized
by Opatz, in 50% yield from phenol 9 and aryl bromide 10
20
under Ma’s optimized conditions for catalytic Ullman-type
coupling.
Recognizing that 1 possesses an element of hidden sym-
metry, we questioned whether our conditions for diaryl ether
formation could be used for its direct synthesis from 11
(
Scheme 2C). This would feature a catalytic aerobic desym-
metrization that could shorten the overall step count by
requiring the preparation of only a single coupling partner.
It would also offer a rare example of aerobic desymmetrization,
21
in which an atom of O is incorporated into the produdct.
2
Herein, we describe the successful execution of this plan and
report a concise and high-yielding synthesis of 1 along these
22
lines.
To investigate our proposed key step, we developed an
asymmetric synthesis of Boc-protected THIQ (17), inspired by
23
the precedent of Noyori (Scheme 3). Namely, amidation of
2 and 13 at increased temperatures without solvent, followed
by a Bischler−Napieralski cyclization, set the stage for Noyori’s
1
23
asymmetric hydrogenation. This introduced the benzylic
stereocenter in 94% ee over a three-step sequence that could be
run on a multigram scale in 70% yield. Despite our efforts to
use free amine 16 or its methyl-substituted derivative (not
shown) in the subsequent aerobic catalysis, these substrates
afforded intractable mixtures at complete consumption of the
starting material. Therefore, we advanced the synthesis by Boc
protection to afford 17 before conducting the key step. Under
6a
our previously optimized conditions, aerobic oxidative cou-
pling is complete within 4 h at room temperature using an
applied pressure of O2 (1 atm). The catalyst system is
composed of 4 mol % of CuPF and 5 mol % of DBED in
6
CH Cl . Whereas ortho-quinone 19 is the immediate product
2
2
of coupling, we use a reductive workup, consisting of a satu-
rated aqueous solution of sodium dithionite (Na S O ) to
2
2
4
effect in situ reduction. This leads to the corresponding
coupled catechol 20 in a 60% isolated yield on a 400 mg scale.
Notably, the yield of this process improves to 75% when
conducted in the presence of 4 Å MS, highlighting the
beneficial effects of running these reactions in the presence of a
feature of many simple neuromuscular relaxants, which contain
17b
quaternized ammonium cations separated by ∼10 carbon
desiccant.
Subsequent methylation of the catechol and
1
6
atoms.
reduction of the N-Boc groups under standard conditions
furnished (S,S)-tetramethylmagnolamine (1) in a longest linear
sequence (LLS) of 7 steps that proceeded in 21% overall
yield. This compares favorably to the only previous synthesis of
1 by Opatz (Scheme 2C), which required 16 total steps and a
Although this subfamily of THIQs has been extensively
studied, questions remain about their biosynthesis and how
the associated oxidases create the defining diaryl ethers
1
3a
(
Scheme 2B). Free radical reactions of phenoxyl radicals
19
favor C−C instead of C−O bond formation, reflecting
LLS of 8 steps that proceeded in 14% overall yield. Our route
takes advantage of the target’s pseudosymmetry and forms
the key aryl ether linkage at room temperature by selectively
oxidizing two aromatic C−H bonds of 1 equiv of the starting
the favorable localization of spin density on the less electro-
1c,17
negative carbons of the aromatic ring.
Little is known
about how these enzymes change selectivity to promote
C−O bond formation and to what extent the metal center is
involved in the bond forming event. This underscores a
more general challenge of using phenols in oxidative C−O
bond forming reactions as it is easy to trigger competitive
free-radical pathways that erode selectivity. Instead, more
commonly practiced aryl ether syntheses are isohypsic, includ-
ing Ullman or Buchwald−Hartwig cross-coupling reac-
tions that employ an oxidized aromatic halide as the cou-
material and the phenol O−H on another. Because O is the
2
terminal reductant, H O is the only stoichiometric byproduct
2
of the reaction.
In conclusion, we have described an asymmetric total
synthesis of (S,S)-tetramethylmagnolamine (1) that features a
catalytic aerobic desymmetrization of phenols. Despite many
of its attributes, O remains underutilized in complex molecule
2
synthesis due, in part, to persistent challenges of controlling
selectivity. Our work highlights the beneficial effects of
bioinspired metal coordination in overcoming this challenge
and also highlights the unique reactivity of Cu in catalyzing
18
pling partner (Scheme 2C). Cross-coupling reactions of
this family have been extensively studied, but their persis-
tent use of stoichiometric base and increased reaction
B
DOI: 10.1021/acs.orglett.9b03559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. (A) Tetrahydroisoquinoline Alkaloids with Diaryl Ether Linkages, (B) Proposed Biosynthesis of the Diaryl Ether
Linkages, and (C) Previous Synthesis of (S,S)-Tetramethylmagnolamine and This Work
a
Scheme 3. Forward Synthesis
a
Reagents and conditions: (a) neat, 200 °C, 2 h, 91%; (b) POCl (6 equiv), MeCN, reflux, 1 h; (c) 15 (0.2 mol %), HCO H/NEt (5:2), DMF, rt,
3
2
3
1
2 h, 78% over two steps, 94% ee; (d) Boc O (1.1 equiv), MeOH, rt, 12 h, 89%; (e) [Cu(MeCN) ](PF ) (4 mol %), DBED (5 mol %), 4 Å MS,
2
4
6
CH Cl , O (1 atm), rt, 4 h, then Na S O workup, 75%; (f) MeI (3.0 equiv), Cs CO (3.0 equiv), DMSO, rt, 12 h; (g) LiAlH (10.0 equiv), THF,
2
2
2
2
2
4
2
3
4
reflux, 12 h, 44% over two steps.
C−O bond formation during phenolic oxidation. We see
many opportunities to extend this chemistry to other diaryl
ether targets, including additional members of the THIQ-ether
subfamily, and work toward this goal will be reported in due
course.
ASSOCIATED CONTENT
■
* Supporting Information
S
1
5b
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03559.
C
DOI: 10.1021/acs.orglett.9b03559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures and characterization data
Letter
(12) For a more detailed study of the C−O coupling step, see:
Huang, Z.; Lumb, J.-P. Angew. Chem., Int. Ed. 2016, 55, 11543−
(PDF)
1
(
1547.
Copies of NMR spectra (PDF)
13) (a) Weber, C.; Opatz, T. Bisbenzylisoquinoline Alkaloids. In
The Alkaloids: Chemistry and Biology; Knolker, H.-J., Ed.; Academic
̈
AUTHOR INFORMATION
Corresponding Author
Press, 2019; Vol. 81, pp 1−114, Chapter 1. (b) Shamma, M. The
Isoquinoline Alkaloids Chemistry and Pharmacology; Elsevier, 2012;
Vol. 25.
■
*
E-mail: jean-philip.lumb@mcgill.ca.
ORCID
(
14) Otto, N.; Ferenc, D.; Opatz, T. J. Org. Chem. 2017, 82, 1205−
1217.
(
15) (a) Kupchan, S. M.; Liepa, A. J.; Kameswaran, V.; Sempuku, K.
Jean-Philip Lumb: 0000-0002-9283-1199
Present Address
J. Am. Chem. Soc. 1973, 95, 2995−3000. (b) Xu, W.; Huang, Z.; Ji, X.;
Lumb, J.-P. ACS Catal. 2019, 9, 3800−3810.
†
(16) Alkaloids. In Medicinal Natural Products; Dewick, P. M., Ed.;
Department of Chemistry, New York University, Silver
2
009; pp 311−420.
17) (a) Quideau, S.; Deffieux, D.; Pouyseg
of Phenols and Phenol Ethers. In Comprehensive Organic Synthesis II,
Center for Arts and Science, 100 Washington Square East,
New York, NY 10003, United States.
Notes
(
́
u, L. Oxidative Coupling
2
nd ed.; Knochel, P., Ed.; Elsevier: Amsterdam, 2014; pp 656−740.
The authors declare no competing financial interest.
(b) Esguerra, K. V. N.; Fall, Y.; Petitjean, L.; Lumb, J.-P. J. Am. Chem.
Soc. 2014, 136, 7662−7668.
(
18) (a) Evano, G.; Wang, J.; Nitelet, A. Org. Chem. Front. 2017, 4,
ACKNOWLEDGMENTS
■
2
480−2499. (b) Pitsinos, E. N.; Vidali, V. P.; Couladouros, E. A. Eur.
Financial support was provided by the Natural Sciences and
Engineering Council (NSERC) of Canada (Discovery Grant to
J.-P.L.); the Fonds de Recherche Quebecois Nature et
Technologies (FRQNT) (Team Grant to J.-P.L.); McGill
University Faculty of Science (Milton Leong Fellowship in
Science to Z.H.), and the FRQNT Center for Green
Chemistry and Catalysis (fellowship to X.J.).
J. Org. Chem. 2011, 2011, 1207−1222.
(
(
19) Blank, N.; Opatz, T. J. Org. Chem. 2011, 76, 9777−9784.
20) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799−3802.
(21) For selected examples of desymmetrization in biosynthesis or
bioinspired synthesis, see: (a) Hu, X.; Maimone, T. J. J. Am. Chem.
Soc. 2014, 136, 5287−5290. (b) Miyabe, H.; Torieda, M.; Inoue, K.;
Tajiri, K.; Kiguchi, T.; Naito, T. J. Org. Chem. 1998, 63, 4397−4407.
(
c) Smith, W. L.; Urade, Y.; Jakobsson, P.-J. Chem. Rev. 2011, 111,
5
1
(
821−5865. (d) Goodhue, C. T.; Schaeffer, J. R. Biotechnol. Bioeng.
REFERENCES
■
971, 13, 203−214.
(
1) (a) Que, L.; Tolman, W. B. Nature 2008, 455, 333−340.
b) Trammell, R.; Rajabimoghadam, K.; Garcia-Bosch, I. Chem. Rev.
22) A version of this work first appeared on the ChemRxiv
(
repository: Huang, Z.; Ji, X.; Lumb, J.-P. ChemRxiv Preprint 2019,
DOI: 10.26434/chemrxiv.9956213.
(
2
019, 119, 2954−3031. (c) Allen, S. E.; Walvoord, R. R.; Padilla-
Salinas, R.; Kozlowski, M. C. Chem. Rev. 2013, 113, 6234−6458.
23) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
(
(
d) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851−863.
Am. Chem. Soc. 1996, 118, 4916−4917.
e) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev. 2005, 105,
2
(
329−2364.
2) Stahl, S. S.; Alsters, P. L. Liquid Phase Aerobic Oxidation
Catalysis: Industrial Applications and Academic Perspectives; Wiley-
VCH: Weinheim, 2016.
(3) Borden, W. T.; Hoffmann, R.; Stuyver, T.; Chen, B. J. Am. Chem.
Soc. 2017, 139, 9010−9018.
(
4) (a) Esguerra, K. V. N.; Xu, W.; Lumb, J.-P. Chem. 2017, 2, 533−
549. (b) Esguerra, K. V. N.; Lumb, J.-P. Angew. Chem., Int. Ed. 2018,
5
(
7, 1514−1518.
5) For review articles, see: (a) Esguerra, K. V. N.; Lumb, J.-P.
Synthesis 2019, 51, 334−358. (b) Huang, Z.; Lumb, J.-P. ACS Catal.
019, 9, 521−555.
6) For related examples, see: (a) Esguerra, K. V. N.; Fall, Y.; Lumb,
2
(
J.-P. Angew. Chem. 2014, 126, 5987−5991. (b) Huang, Z.; Kwon, O.;
Huang, H.; Fadli, A.; Marat, X.; Moreau, M.; Lumb, J.-P. Angew.
Chem., Int. Ed. 2018, 57, 11963−11967.
(7) (a) Elwell, C. E.; Gagnon, N. L.; Neisen, B. D.; Dhar, D.; Spaeth,
A. D.; Yee, G. M.; Tolman, W. B. Chem. Rev. 2017, 117, 2059−2107.
(
b) Solomon, E. I.; Heppner, D. E.; Johnston, E. M.; Ginsbach, J. W.;
Cirera, J.; Qayyum, M.; Kieber-Emmons, M. T.; Kjaergaard, C. H.;
Hadt, R. G.; Tian, L. Chem. Rev. 2014, 114, 3659−3853.
(8) (a) Borovansky, J.; Riley, P. A. Melanins and Melanosomes; Wiley-
VCH: Weinheim, 2011. (b) Esguerra, K. V. N.; Lumb, J.-P. Synlett
015, 26, 2731−2738.
9) Mirica, L. M.; Vance, M.; Rudd, D. J.; Hedman, B.; Hodgson, K.
O.; Solomon, E. I.; Stack, T. D. P. Science 2005, 308, 1890−1892.
10) For review articles, see: (a) Rolff, M.; Schottenheim, J.; Decker,
2
(
(
H.; Tuczek, F. Chem. Soc. Rev. 2011, 40, 4077−4098. (b) Mirica, L.
M.; Ottenwaelder, X.; Stack, T. D. P. Chem. Rev. 2004, 104, 1013−
1
(
046.
11) Askari, M. S.; Esguerra, K. V. N.; Lumb, J.-P.; Ottenwaelder, X.
Inorg. Chem. 2015, 54, 8665−8672.
D
DOI: 10.1021/acs.orglett.9b03559
Org. Lett. XXXX, XXX, XXX−XXX