Improved and Flexible Synthetic Access to the Spiroindole Backbone of Cebranopadol

Article abstract of DOI:10.1021/acs.orglett.0c02234

By changing the dimethylamino to a nitro group, a novel synthetic access to the spirocyclic opioid analgesic cebranopadol was developed that is much more efficient compared with the established route. On the basis of the α-acidity of α-nitrotoluene, the two-fold Michael addition to acrylate gave an acyclic precursor compound, which was easily transformed by Dieckmann condensation and decarboxylation to the cyclohexanone derivative needed for the annulation of the indole ring by an oxa-Pictet-Spengler reaction. As an additional benefit, the reduction of the nitro group furnished an amine, which could be late-stage-diversified to carboxamides, sulfonamides, ureas, and N-alkyl congeners. The transformation of the nitro group at the spirocyclic scaffold to the dimethylamino function of the actual title compound was achieved in one step with zinc/formic acid/formaldehyde in 83% yield.

Full text of DOI:10.1021/acs.orglett.0c02234

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Letter
Improved and Flexible Synthetic Access to the Spiroindole
Backbone of Cebranopadol
Daniel Wachtendorf, Marc Schmidtmann, and Jens Christoffers*
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Supporting Information
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ABSTRACT: By changing the dimethylamino to a nitro group, a
novel synthetic access to the spirocyclic opioid analgesic
cebranopadol was developed that is much more efficient compared
with the established route. On the basis of the α-acidity of α-
nitrotoluene, the two-fold Michael addition to acrylate gave an
acyclic precursor compound, which was easily transformed by
Dieckmann condensation and decarboxylation to the cyclohexanone
derivative needed for the annulation of the indole ring by an oxa-Pictet−Spengler reaction. As an additional benefit, the reduction of
the nitro group furnished an amine, which could be late-stage-diversified to carboxamides, sulfonamides, ureas, and N-alkyl
congeners. The transformation of the nitro group at the spirocyclic scaffold to the dimethylamino function of the actual title
compound was achieved in one step with zinc/formic acid/formaldehyde in 83% yield.
a
Scheme 2. Preparation of Nitroketone 5
ebranopadol (1b) is a novel opioid analgesic presently in
Cclinical trials for the therapy of a variety of different acute
and chronic pain states.1 Its side-effect profile is superior to
those of other typical opioids, and it is predominantly
discussed for the treatment of pain related to cancer.2
Cebranopadol (1b) was discovered in 2004 by chemists
from the German pharmaceutical company Gru
̈
nenthal.3 The
backbone structure of compound 1b is a spiro[cyclohexan-
1,1′-pyrano[3,4-b]indole] (Scheme 1). Compound 1b is
achiral, and it is the diastereoisomer with the 1,4-disubstituted
cyclohexane ring in the relative trans configuration. The
established synthesis of cebranopadol (1b) utilizes an oxa-
Pictet−Spengler reaction of a 3-(hydroxyethyl)indole with
cyclohexanone derivative 2 as a key step, which is accessed
from acetal-protected α-aminonitrile 3.4 Therefore, the
Scheme 1. Established Synthetic Route to Cebranopadol
(1b) from Aminonitrile 3 as Developed by Grunenthal and
̈
a
New Strategy via Nitro Compounds 4−6 (This Work)
Reagents and conditions: (a) 5.0 equiv of H2O2 (30% in H2O), 3.0
equiv of (F3CCO)2O, 0.5 equiv of urea, 4.0 equiv of Na2HPO4·2H2O,
MTBE, 50 °C, 16 h. (b) 2.5 equiv of methyl acrylate, 0.5 equiv of
DBU, CH2Cl2, 40 °C, 16 h. (c) 1.7 equiv of NaH, 0.1 equiv of
MeOH, THF, 50 °C, 1 h. (d) 3.0 equiv of LiBr, 2.0 equiv of CSA,
DMPU, 100 °C, 16 h.
Received: July 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02234
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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Scheme 3. Spirocyclization by oxa-Pictet−Spengler
Scheme 4. Reduction of the Nitro Group and Reductive
Methylation
a
Reaction Furnishing Separable trans Isomers 4a−d and cis
a
Isomers 11a−c
a
Reagents and conditions: (a) 40 equiv of Zn, 40 equiv of HCO2H,
a
Reagents and conditions: (a) (1) 1.2 equiv of TFA, CH2Cl2, 50 °C,
MeOH, 50 °C, 16 h. (b) (1) As (a), (2) + 40 equiv of HCO2H, 40
equiv of H2CO (37% in H2O), 70 °C, 16 h. (c) 8 equiv of HCO2H,
3.3 equiv of H2CO (37% in H2O), MeOH, 70 °C, 16 h.
16 h. (2) + NaOH (1 mol/L in H2O), 0 °C, 0.5 h.
ketone 5 is readily accessed by the two-fold conjugated
addition of α-nitrotoluene (6) to methyl acrylate followed by
Dieckmann condensation and ester saponification/decarbox-
ylation. This is much more convenient and less complicated
than the synthesis of amino-ketone 2.
The synthesis started with the preparation of α-nitrotoluene
(6) in 96% yield (Scheme 2), which was accomplished by the
oxidation of oxime 7 following a modified literature
procedure.5 The next two steps followed literature protocols
recently reported for the analogous conversion of nitroethane.6
The two-fold conjugated addition to methyl acrylate was DBU-
catalyzed and gave the pimelic acid ester 8 in 89% yield, which
was submitted to Dieckmann condensation with a stoichio-
metric amount of NaH in THF,7 furnishing the β-oxoester 9
(54%) exclusively as the enol tautomer. The addition of some
MeOH led to the formation of NaOMe and facilitated the
reaction. The next step, the ester saponification with
subsequent decarboxylation, required tedious optimization.
After unsatisfying experimentation with several alternative
procedures (see the Supporting Information for details), we
finally succeeded with a modified Krapcho protocol in DMPU
which followed some literature precedence.8 The yield (61%)
was moderate, but the starting material could be recovered
(i.e., 99% based on recovered starting material (brsm)).
The 3-(2-hydroxyethyl)indole derivatives 10a−d were
accessed according to a literature report by Fischer indolization
from the respective phenylhydrazine derivatives and dihy-
drofurane (as a precursor to 4-hydroxybutanal).9 The oxa-
Pictet−Spengler reaction proceeded straightforwardly when
converting stoichiometric amounts of the nitroketone 5 with
the indole derivatives 10a−d in TFA−CH2Cl2 (Scheme 3).10
In general, the trans diastereoisomers 4a−d were hardly
soluble and precipitated from the reaction mixture and were
collected by filtration. The supernatants contained the cis
diastereoisomers 11a−c together with residual amounts of the
trans isomers 4a−d, which were separated and purified by
chromatography. In the case of the methoxy-substituted
compound, the cis isomer 11d was not formed. The relative
configuration of one representative was established by the
Figure 1. ORTEP representation of the structure of compound cis-
11a in the solid state (as the solvate with DMSO-d6). Ellipsoids are at
the 50% probability level. Hydrogen atoms and DMSO-d6 are omitted
for clarity.
dimethylamino function was already installed in a very early
stage of the overall sequence by the conversion of
monoprotected 1,4-cyclohexanedione with HNMe2/HCN to
furnish compound 3 (67−99% yield).4a This intermediate was
then converted with a phenyl Grignard reagent (28−99%
yield) and deprotected to give ketone 2 (66−99% yield).4a The
spirocyclization yielded 84% of trans diastereoisomer 1b.4b
Herein we disclose an alternative approach to cebranopadol
(1b), which first generates the nitro-congener 4 by an oxa-
Pictet−Spengler reaction of cyclohexanone derivative 5. There
are two significant advantages of this new strategy: (1) The
nitro group can, of course, be transformed into the
dimethylamino function of the actual target compound 1b.
As an additional benefit, other nitrogen functionalizations
could be easily installed, for example, N-alkyl or N-acyl
derivatives, and thus a late-stage diversification of the
spirocyclic scaffold is now feasible. (2) Second, the nitro-
B
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the preparation of cebranopadol 1b from nitro compound 4b.
The 83% yield fully satisfied our expectations.
Scheme 5. Further Derivatization of the Primary Amino
Function of trans Isomer 12
a
As introductorily proposed, one advantage of our new route
is the late-stage derivatization of the spirocyclic scaffold.
Therefore, standard transformations of the primary amino
group, which are often found in the field of medicinal
chemistry, were exemplarily performed for compound 12
(Scheme 5): carbox- and sulfonamide formation, preparation
of ureas from isocyanates, and alkylation reactions by the
reductive amination of aldehydes. First, acetamide 13 was
formed in 57% yield by the treatment of amine 12 with Ac2O.
The amidation of compound 12 with an aromatic carboxylic
acid utilized EDC as the coupling reagent (53% of product
14). Coupling of the aliphatic carboxylic acid (N-Boc-L-
neopentylglycine, N-Boc-L-NpgOH)12 with EDC as the
reagent gave amide 15 with a superior result (83% yield).
Sulfonamide 16 was obtained in 68% yield from BrosCl and
NEt3. Conversion with an arylisocyanate in boiling THF gave
urea 17 in 66% yield. Finally, reductive amination with
benzaldehyde and isobutyraldehyde with NaCNBH3 in an
acidic environment13 gave the secondary amines 18a (R = Ph,
63%) and 18b (R = iPr, 33%).
In summary, a novel route to the Active Pharmaceutical
Ingredient (API) cebranopadol 1b was introduced. The key
strategy was the use of a nitro function as a precursor for the
dimethylamino group. The reduction/reductive amination of
the nitro function is achieved with zinc/formic acid/form-
aldehyde in one step, furnishing the title compound 1b in 83%
yield. The nitro group furthermore allows for a straightforward
approach to ketone 5 by Dieckmann condensation of the
acyclic diester 8, which is accessed by a two-fold Michael
addition of α-nitrotoluene 6 to methyl acrylate. Compared
with the preparation of the ketone 2 with the dimethylamino
group present, our new approach is comparably efficient.
However, the main advantage is that the nitro group at the
spirocyclic scaffold allows for late-stage functionalization after
the reduction to the primary amino group, as was shown
exemplarily with the formation of carboxamides 13−15, a
sulfonamide 16, a urea 17, and the alkylated congeners 18 by
reductive alkylations with aldehydes.
ASSOCIATED CONTENT
a
■
Reagents and conditions: (a) 1.2 equiv of Ac2O, THF, 23 °C, 16 h.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02234.
(b) 2 equiv of ArCO2H (for 14, Ar = 4-IC6H4) or 2 equiv of RCO2H
(for 15, RCO2H = N-Boc-L-NpgOH), 2 equiv of EDC·HCl, 3 equiv
of NEt3, THF, 23 °C, 16 h. (c) 2 equiv of BrosCl (Bros = 4-
BrC6H4SO2), 2 equiv of NEt3, THF, 23 °C, 16 h. (d) 2 equiv of
ArNCO (Ar = 2-CF3C6H4), THF, 75 °C, 16 h. (e) 1.1 equiv of
RCHO, 0.5 equiv of ZnCl2, 1.1 equiv of NaCNBH3, THF, 23 °C, 16
h.
Synthesis, analytical data, and NMR spectra (PDF)
Accession Codes
CCDC 2012244 contains the supplementary crystallographic
data for this paper. These data can be obtained 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
single-crystal X-ray structure analysis of the cis isomer 11a (X
= H, Figure 1; see the Supporting Information for details).
The trans isomer 4a was subsequently submitted to the
reduction of the nitro group with zinc to furnish the primary
̈
amine 12 (89%) (Scheme 4). The Bronsted acid formic acid
was chosen because it was also used in the next step, the
reductive amination with formaldehyde according to an
Eschweiler−Clarke protocol,11 which gave the respective
dimethylamino derivative 1a (60% from 12). Consequently,
the two reductions were then performed sequentially in one
flask, and, indeed, the yield was superior to that for the two-
step procedure via compound 12 (product 1a, 64% from 4a).
Therefore, we only used the two-step−one-flask protocol for
AUTHOR INFORMATION
■
Corresponding Author
Jens Christoffers − Institut fur Chemie, Universitat Oldenburg,
̈
̈
D-26111 Oldenburg, Germany; orcid.org/0000-0003-
1433-6579; Email: jens.christoffers@uol.de; Fax: +49 441
798 3873
C
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Org. Lett. XXXX, XXX, XXX−XXX

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Authors
pubs.acs.org/OrgLett
Letter
Daniel Wachtendorf − Institut fu
Oldenburg, D-26111 Oldenburg, Germany
r Chemie, Universitat
̈
r Chemie, Universitat
̈
Marc Schmidtmann − Institut fu
̈
̈
Oldenburg, D-26111 Oldenburg, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02234
Notes
The authors declare no competing financial interest.
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