Total Synthesis of (-)-Oxycodone via Anodic Aryl-Aryl Coupling

Article abstract of DOI:10.1021/acs.orglett.9b00419

A fully regio- and diastereoselective electrochemical 4a-2′-coupling of a 3′,4′,5′-trioxygenated laudanosine derivative enables the synthesis of the corresponding morphinandienone. This key intermediate is further transformed into (-)-oxycodone through conjugate nucleophilic substitution for E-ring closure and [4 + 2] cycloaddition with photogenerated singlet oxygen to accomplish diastereoselective hydroxylation at C-14. The anodic transformation provides high yields and can be performed under constant current conditions both in a simple undivided cell or in continuous flow.

Full text of DOI:10.1021/acs.orglett.9b00419

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of (−)-Oxycodone via Anodic Aryl−Aryl Coupling
Alexander Lipp, Maximilian Selt, Dorota Ferenc, Dieter Schollmeyer, Siegfried R. Waldvogel,
and Till Opatz*
Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: A fully regio- and diastereoselective electro-
chemical 4a−2′-coupling of a 3′,4′,5′-trioxygenated laudanosine
derivative enables the synthesis of the corresponding
morphinandienone. This key intermediate is further trans-
formed into (−)-oxycodone through conjugate nucleophilic
substitution for E-ring closure and [4 + 2] cycloaddition with
photogenerated singlet oxygen to accomplish diastereoselective
hydroxylation at C-14. The anodic transformation provides high yields and can be performed under constant current conditions
both in a simple undivided cell or in continuous flow.
xycodone is a semisynthetic opioid derived from
naturally occurring thebaine and is commercially
several years working on this electrosynthetic challenge.7f,9 We
recently discovered that the desired 4a−2′-coupled morphi-
nandienones can be obtained from laudanosine derivatives
bearing a 3′,4′,5′-trioxygenated10 benzylic moiety with
orthogonal O-protecting groups that create a sufficient
electronic differentiation within the aromatic ring (Scheme
1B).11 Herein, we report the optimization of this anodic
coupling and its application to the asymmetric synthesis of
non-natural opioids. (−)-Oxycodone was chosen as exemplary
target because of its challenging structure and its outstanding
medicinal relevance.
O
produced on a multiton scale.1 It is prescribed as a strong
analgesic, e.g., for pain management in cancer patients and has
a significantly higher oral bioavailability than morphine.2 Due
to their outstanding medicinal relevance in combination with
an attractive molecular structure, the morphinan alkaloids are
appealing synthetic targets, and many approaches toward
morphine and its congeners have been devised.3 However, in
view of recent developments within the United States, it must
also be mentioned that severe problems can arise from opiate
addiction and abuse.4
First, an optimization of the anodic coupling with respect to
electrode material and solvent was undertaken (Table 1).
The best results were obtained using a boron-doped
diamond (BDD) anode in combination with a platinum
cathode in MeCN containing a small amount of aqueous HBF4
as acidic electrolyte to prevent amine oxidation. In fact, BDD is
often a superior choice for dehydrogenative couplings and has
emerged as powerful electrode material for numerous trans-
formations.12 In contrast, the molybdenum anode,13 which was
recently shown to be a suitable material for the dehydrogen-
ative coupling of oxygenated arenes, did not afford the desired
product. Rapid passivation of the electrode surface was
observed instead, and 81% of starting material could be
recovered. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP), a fre-
quently used solvent in organic electrochemistry, e.g., for
dehydrogenative couplings,14 proved to be unsuitable for the
coupling of laudanosine derivatives. Complex mixtures
containing neither starting material nor product were obtained.
An extensive screening of reaction parameters comprising
temperature, current density, reactant concentration, and
stoichiometry of acidic additive was performed both in batch
electrolysis and in continuous flow mode (see the Supporting
Information). Under optimized conditions, morphinandienone
The biosynthesis of morphine proceeds through the
intramolecular oxidative coupling of (R)-reticuline to salutar-
idine.3b The imitation of this enzyme-mediated coupling is
hampered by the fact that it can form four different
regioisomers, of which only the 4a−2′-coupled product can
be further converted into morphine alkaloids (Scheme 1A). In
the past decades, many approaches toward mimicking this
challenging coupling using conventional oxidants such as
VOCl3, K3Fe(CN)6, MnO2−silica, Ag2CO3−Celite, or Tl-
(CO2CF3)3 were undertaken.5 However, these attempts
suffered from relatively low yields or undesired regioselectivity.
Electrochemistry provides a versatile tool box for organic
synthesis and offers an appealing alternative to the use of
stoichiometric quantities of chemical oxidants.6 The anodic
coupling of laudanosine (O-methoxylated reticuline) is fully
selective for the 4a position, thereby granting access to the
desired morphinandienone skeleton.7 However, for steric and
electronic reasons, it is also inherently 6′-selective. As the
obtained isosalutaridine-type products (4a−6′-coupled) do not
have an oxygen substituent ortho to the newly formed bond,
they cannot be converted into morphine alkaloids via E-ring
closure. All attempts to overcome the troublesome 6′-
selectivity failed, and a 4a−2′-coupling which would provide
elegant biomimetic access to morphine alkaloids remained
Received: January 31, 2019
elusive.7d−f,8 In a joint effort with Schafer, our groups spent
̈
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00419
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Selective Synthesis of a 4a-2′-Coupled Morphinandienone through a Combination of Electrochemistry and
Substrate Design: Application to the Total Synthesis of (−)-Oxycodone
a
( )-2 can be obtained under constant current conditions in an
undivided cell (beaker-type, up to 69% yield) or in continuous
flow15 (up to 57% yield).
Table 1. Screening of Electrode Material and Solvent
Considering the complexity of the transformation, this regio-
and diastereoselective anodic oxidation affords appreciable
yields. Furthermore, it is operationally simple and does not
require a redox mediator or any supporting electrolytes other
than aqueous HBF4. The C−C bond formation demands an
overlap of both π systems involved, and the resulting parallel
positioning of the two aromatic rings leads to the observed
diastereoselectivity. The regioselectivity (favoring coupling
between positions 4a and 2′) is presumably induced by
electronic differentiation within both aromatic moieties.11
Following a procedure previously reported by our group,11,16
1-benzyl-1,2,3,4-tetrahydroisoquinoline (R)-1 was prepared
from naturally occurring and inexpensive starting materials
(methyl gallate and vanillin via homoveratrylamine) using a
Noyori asymmetric transfer hydrogenation.17 Thus, being
based on natural feedstocks, the devised synthesis of
(−)-oxycodone adds to the emerging field of xylochemistry.18
Laudanosine derivative (R)-1 was converted into the
corresponding morphinandienone (+)-2 using the optimized
anodic coupling (Scheme 2). E-Ring closure was accomplished
via selective 1,2-reduction of the carbonyl group under Luche
conditions, deacetylation, and subsequent conjugate nucleo-
philic substitution enabled by activation of the intermediate
allylic alcohol with N,N-dimethylformamide dineopentyl
b
no.
anode
graphite
glassy carbon
Pt
cathode
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN/DCM (2:1)
HFIP
yield (%)
1
2
3
4
5
6
7
8
Pt
Pt
Pt
Pt
Pt
Ni
60
59
59
c
Mo
0
BDD
BDD
BDD
BDD
BDD
graphite
Mo
67
58
51
56
e
d
steel
Pt
Pt
Pt
Pt
9
10
11
HFIP
HFIP
e
e
a
Reactions performed according to the general procedure given in the
Supporting Information (for Table S1) using ( )-1 (0.75 mmol, 1.0
equiv), HBF4 (48% aq, 4.0 equiv), and 75 mL of solvent in an
undivided cell; Yields after chromatographic purification, full
b
c
d
e
conversion. 81% of ( )-1 recovered. Stainless steel. Complex
mixtures, product not detectable.
B
DOI: 10.1021/acs.orglett.9b00419
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Total Synthesis of (−)-Oxycodone
a
Procedures: (a) constant current electrolysis, undivided cell, BDD anode, Pt cathode, j = 1.5 mA/cm2, Q = 2.2 F, MeCN, HBF4, 0 °C; (b) CeCl3·
7H2O, NaBH4, MeOH, 0 °C; (c) K2CO3, MeOH, rt; (d) N,N-dimethylformamide dineopentyl acetal, dioxane, 60 °C; (e) TPP, O2, TFA, CH2Cl2,
blue LED, rt; (f) Pd/C, H2 (1 atm), CH2Cl2, rt; (g) 5-chloro-1-phenyl-1H-tetrazole, K2CO3, DMF, 70 °C; (h) Pd/C, H2 (30 bar), CH2Cl2/EtOH,
rt; tetrahydroisoquinoline (R)-1 was prepared following a procedure previously described by our group (ref 11); X-ray molecular structures
(ORTEP, ellipsoids displayed with 50% probability) were obtained for the racemic samples ( )-5 (CCDC 1894339), ( )-6 (CCDC 1894340),
and ( )-7 (CCDC 1894341).
acetal.3i The required additional hydroxy group could be
Accession Codes
introduced using a one-pot sequence including diastereose-
lective [4 + 2] cycloaddition of singlet oxygen to the dienol
CCDC 1894339−1894341 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
ether’s double bonds and subsequent reduction of the initially
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
formed endoperoxide Int-4.3s,19 In-situ generation of singlet
oxygen was accomplished under visible-light irradiation (blue
LED) via energy transfer from photoexcited tetraphenylpor-
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
phyrin (TPP).
Hydrogenation on Pd/C led to rapid O−O-bond cleavage in
Int-4 with concomitant hydrogenation of the CC-double
bond and O-debenzylation. Intermediate Int-5 was converted
into (−)-oxycodone via another Pd-catalyzed hydrogenation of
the preformed tetrazolyl ether (−)-6.10,20
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: opatz@uni-mainz.de.
ORCID
In summary, a total synthesis of (−)-oxycodone was devised
that relies on the regio- and diastereoselective formation of a
4a−2′-coupled morphinandienone through a combination of
electrochemistry and substrate design. The remarkably
selective anodic coupling is operationally simple, almost
reagent-free, and can be performed in batch or in continuous
flow. E-Ring closure via conjugate nucleophilic substitution
and introduction of the required 14-hydroxy group via [4 + 2]
cycloaddition with photogenerated singlet oxygen also
proceeded with complete diastereoselectivity.
Siegfried R. Waldvogel: 0000-0002-7949-9638
Till Opatz: 0000-0002-3266-4050
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the support from the Advanced Lab of
Electrochemistry and Electrosynthesis (ELYSION, financed by
the Carl Zeiss Foundation) and by the Rhineland Palatinate
Natural Products Research Center. We thank Dr. Johannes C.
Liermann (Mainz) for NMR spectroscopy and Dr. Christopher
Kampf (Mainz) for mass spectrometry.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00419.
REFERENCES
■
(1) (a) Hudlicky, T. Can. J. Chem. 2015, 93, 492. (b) Berenyi, S.;
Csutoras, C.; Sipos, A. Curr. Med. Chem. 2009, 16, 3215.
(c) Halvorsen, H.; Lovli, T. WO2009004491, 2009. (d) Weber, B.;
Sahli, S. WO 2011117172, 2011. (e) Keskeny, E. M.; Mencel, J. J.;
Dung, J.-S. WO 2012003468, 2012.
(2) (a) Riley, J.; Eisenberg, E.; Mu
Arendt-Nielsen, L. Curr. Med. Res. Opin. 2008, 24, 175. (b) Ordon
Detailed optimization studies, X-ray molecular structures
of important intermediates, experimental procedures,
HPLC chromatograms for determination of enantio-
meric excess, and copies of NMR spectra (PDF)
̈
ller-Schwefe, G.; Drewes, A. M.;
́
̃
ez
C
DOI: 10.1021/acs.orglett.9b00419
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
́
́
Gallego, A.; Gonzalez Baron, M.; Espinosa Arranz, E. Clin. Transl.
Oncol. 2007, 9, 298. (c) King, S. J.; Reid, C.; Forbes, K.; Hanks, G.
Palliat. Med. 2011, 25, 454.
derivatives; see: Bobbitt, J. M.; Noguchi, I.; Ware, S. R.; Chiong, K.
N.; Huang, S. J. J. Org. Chem. 1975, 40, 2924.
(8) (a) Falck, J. R.; Miller, L. L.; Stermitz, F. R. Tetrahedron 1974,
30, 931. (b) Klunenberg, H. PhD Thesis, Westfalische Wilhelms-
̈
̈
(3) Selected reviews: (a) Rinner, U.; Hudlicky, T. In Alkaloid
Synthesis; Knolker, H.-J., Ed.; Springer: Berlin, 2012; p 33. (b) Novak,
̈
̈
̈
Universitat Munster, Munster, 1981.
(9) Geffe, M. PhD Thesis, Johannes Gutenberg-Universitat Mainz,
Mainz, 2016.
̈
̈
B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org.
Chem. 2000, 4, 343. (c) Blakemore, P. R.; White, J. D. Chem.
Commun. 2002, 1159. Selected syntheses: (d) Gates, M.; Tschudi, G.
J. Am. Chem. Soc. 1952, 74, 1109. (e) Gates, M.; Tschudi, G. J. Am.
Chem. Soc. 1956, 78, 1380. (f) Grewe, R.; Friedrichsen, W. Chem. Ber.
1967, 100, 1550. (g) Schwartz, M. A.; Mami, I. S. J. Am. Chem. Soc.
1975, 97, 1239. (h) Rice, K. C. J. Org. Chem. 1980, 45, 3135.
(i) White, J. D.; Caravatti, G.; Kline, T. B.; Edstrom, E.; Rice, K. C.;
Brossi, A. Tetrahedron 1983, 39, 2393. (j) Tius, M. A.; Kerr, M. A. J.
Am. Chem. Soc. 1992, 114, 5959. (k) Trost, B. M.; Tang, W. J. Am.
Chem. Soc. 2002, 124, 14542. (l) Stork, G.; Yamashita, A.; Adams, J.;
Schulte, G. R.; Chesworth, R.; Miyazaki, Y.; Farmer, J. J. J. Am. Chem.
Soc. 2009, 131, 11402. (m) Erhard, T.; Ehrlich, G.; Metz, P. Angew.
Chem., Int. Ed. 2011, 50, 3892. (n) Endoma-Arias, M. A. A.; Cox, D.
P.; Hudlicky, T. Adv. Synth. Catal. 2013, 355, 1869. (o) Murphy, B.;
(10) Schwartz, M. A.; Zoda, M. F. J. Org. Chem. 1981, 46, 4623.
(11) Lipp, A.; Ferenc, D.; Gutz, C.; Geffe, M.; Vierengel, N.;
̈
̈
Schollmeyer, D.; Schafer, H. J.; Waldvogel, S. R.; Opatz, T. Angew.
Chem., Int. Ed. 2018, 57, 11055.
(12) (a) Waldvogel, S. R.; Mentizi, S.; Kirste, A. In Radicals in
̈
Synthesis III; Heinrich, M., Gansauer, A., Eds.; Springer: Berlin, 2012;
p 1. (b) Waldvogel, S. R.; Elsler, B. Electrochim. Acta 2012, 82, 434.
Waldvogel, S. R.; Lips, S. ChemElectroChem, 2018, in press,
DOI: 10.1002/celc.201801620. (d) Macpherson, J. V. Phys. Chem.
Chem. Phys. 2015, 17, 2935.
(13) Beil, S. B.; Muller, T.; Sillart, S. B.; Franzmann, P.; Bomm, A.;
̈
Holtkamp, M.; Karst, U.; Schade, W.; Waldvogel, S. R. Angew. Chem.,
Int. Ed. 2018, 57, 2450.
(14) (a) Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.;
Donohoe, T. J. Nat. Rev. Chem. 2017, 1, No. 0088. (b) Kirste, A.;
Schnakenburg, G.; Waldvogel, S. R. Org. Lett. 2011, 13, 3126.
(c) Kirste, A.; Schnakenburg, G.; Stecker, F.; Fischer, A.; Waldvogel,
S. R. Angew. Chem., Int. Ed. 2010, 49, 971. (d) Wiebe, A.; Lips, S.;
Schollmeyer, D.; Franke, R.; Waldvogel, S. R. Angew. Chem., Int. Ed.
2017, 56, 14727.
̌
Snajdr, I.; Machara, A.; Endoma-Arias, M. A. A.; Stamatatos, T. C.;
Cox, D. P.; Hudlicky, T. Adv. Synth. Catal. 2014, 356, 2679. (p) Geffe,
́
M.; Opatz, T. Org. Lett. 2014, 16, 5282. (q) Kimishima, A.; Umihara,
H.; Mizoguchi, A.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2014, 16,
6244. (r) Tissot, M.; Phipps, R. J.; Lucas, C.; Leon, R. M.; Pace, R. D.
M.; Ngouansavanh, T.; Gaunt, M. J. Angew. Chem., Int. Ed. 2014, 53,
13498. (s) Umihara, H.; Yokoshima, S.; Inoue, M.; Fukuyama, T.
̈
̃
(15) (a) Gu
̈
tz, C.; Banziger, M.; Bucher, C.; Galvao, T. R.;
tz, C.;
̈
Chem. - Eur. J. 2017, 23, 6993. (t) Rautschek, J.; Jager, A.; Metz, P.
Org. Lett. 2018, 20, 832.
Waldvogel, S. R. Org. Process Res. Dev. 2015, 19, 1428. (b) Gu
̈
Stenglein, A.; Waldvogel, S. R. Org. Process Res. Dev. 2017, 21, 771.
(16) Werner, F.; Blank, N.; Opatz, T. Eur. J. Org. Chem. 2007, 2007,
3911.
(4) (a) Jayawant, S. S.; Balkrishnan, R. Ther. Clin. Risk Manage.
2005, 1, 77. (b) Rivat, C.; Ballantyne, J. PAIN Reports 2016, 1,
No. e570. (c) Havens, J. R.; Leukefeld, C. G.; DeVeaugh-Geiss, A. M.;
Coplan, P.; Chilcoat, H. D. Drug Alcohol Depend. 2014, 139, 9.
(5) (a) Kametani, T.; Fukumoto, K. Synthesis 1972, 1972, 657.
(b) Kametani, T.; Fukumoto, K.; Satoh, F. Bioorg. Chem. 1974, 3, 430.
(c) Stuart, K. L. Chem. Rev. 1971, 71, 47. (d) Chan, W. W.-C.;
Maitland, P. J. Chem. Soc. C 1966, 753. (e) Jackson, A. H.; Martin, J.
A. J. Chem. Soc. C 1966, 2061. (f) Franck, B.; Dunkelmann, G.; Lubs,
H. Angew. Chem., Int. Ed. Engl. 1967, 6, 1075. (g) Kametani, T.;
Kozuka, A.; Fukumoto, K. J. Chem. Soc. C 1971, 1021. (h) Kametani,
T.; Fukumoto, K.; Kozuka, A.; Yagi, H.; Koizumi, M. J. Chem. Soc. C
1969, 2034. (i) Kametani, T.; Sugahara, T.; Yagi, H.; Fukumoto, K.
Tetrahedron 1969, 25, 3667. (j) Cava, M. P.; Buck, K. T. Tetrahedron
1969, 25, 2795. (k) Schwartz, M. A. Synth. Commun. 1973, 3, 33.
(l) Blasko, G.; Dornyei, G.; Barczai-Beke, M.; Pechy, P.; Szantay, C. J.
Org. Chem. 1984, 49, 1439.
(6) (a) Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117,
13230. (b) Moeller, K. D. Chem. Rev. 2018, 118, 4817. (c) Yoshida, J.-
i.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265.
(d) Yoshida, J.-i.; Shimizu, A.; Hayashi, R. Chem. Rev. 2018, 118,
4702. (e) Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492.
(f) Atobe, M.; Tateno, H.; Matsumura, Y. Chem. Rev. 2018, 118,
4541. (g) Waldvogel, S. R.; Lips, S.; Selt, M.; Riehl, B.; Kampf, C.
(17) (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1996, 118, 4916. (b) Meuzelaar, G. J.; van Vliet,
M. C. A.; Maat, L.; Sheldon, R. A. Eur. J. Org. Chem. 1999, 1999,
2315.
(18) (a) Stubba, D.; Lahm, G.; Geffe, M.; Runyon, J. W.; Arduengo,
A. J.; Opatz, T. Angew. Chem., Int. Ed. 2015, 54, 14187. (b) Kuhlborn,
̈
̈
J.; Konhauser, M.; Groß, J.; Wich, P. R.; Opatz, T. ACS Sustainable
Chem. Eng. 2019, in press, DOI: 10.1021/acssuschemeng.8b06353.
́
́
(19) (a) Lopez, D.; Quinoa, E.; Riguera, R. Tetrahedron Lett. 1994,
̃
́
́
35, 5727. (b) Lopez, D.; Quinoa, E.; Riguera, R. J. Org. Chem. 2000,
̃
65, 4671. (c) Machara, A.; Werner, L.; Leisch, H.; Carroll, R. J.;
Adams, D. R.; Haque, D. M.; Cox, D. P.; Hudlicky, T. Synlett 2015,
26, 2101.
(20) (a) Alves, J. A. C.; Barkley, J. V.; Brigas, A. F.; Johnstone, R. A.
W. J. Chem. Soc., Perkin Trans. 2 1997, 2, 669. (b) Lin, C.-T.; Lee, S.-
S. Synthesis 2015, 47, 2586.
̈
Chem. Rev. 2018, 118, 6706. (h) Wiebe, A.; Gieshoff, T.; Mohle, S.;
Rodrigo, E.; Zirbes, M.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2018,
̈
57, 5594. (i) Mohle, S.; Zirbes, M.; Rodrigo, E.; Gieshoff, T.; Wiebe,
A.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2018, 57, 6018.
(7) (a) Miller, L. L.; Stermitz, F. R.; Falck, J. R. J. Am. Chem. Soc.
1971, 93, 5941. (b) Miller, L. L.; Stermitz, F. R.; Falck, J. R. J. Am.
Chem. Soc. 1973, 95, 2651. (c) Kotani, E.; Tobinaga, S. Tetrahedron
Lett. 1973, 14, 4759. (d) Miller, L. L.; Stewart, R. F.; Gillespie, J. P.;
Ramachandran, V.; So, Y. H.; Stermitz, F. R. J. Org. Chem. 1978, 43,
1580. (e) Klu
̈
nenberg, H.; Schaffer, C.; Schafer, H.-J. Tetrahedron Lett.
̈ ̈
̈
1982, 23, 4581. (f) Brockmeyer, A. PhD Thesis, Westfalische
̈
̈
̈
Wilhelms-Universitat Munster, Munster, 2003. (g) Bentley, T. W.;
Morris, S. J. J. Org. Chem. 1986, 51, 5005. The electrochemical
coupling of reticuline was also investigated, but the yields (∼15%)
were much lower than those obtained with laudanosine or its
D
DOI: 10.1021/acs.orglett.9b00419
Org. Lett. XXXX, XXX, XXX−XXX