Favorskii-Type Rearrangement of the 4,5-Epoxymorphinan Skeleton

Article abstract of DOI:10.1021/acs.orglett.8b00288

The aldol condensation of naltrexone with various aryl aldehydes gives the corresponding 7-benzylidenenaltrexone derivatives in high yields. However, novel C-ring-contracted morphinan compounds were produced when 2-pyridinecarboxaldehyde or its related an

Full text of DOI:10.1021/acs.orglett.8b00288

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Favorskii-Type Rearrangement of the 4,5-Epoxymorphinan Skeleton
Noriki Kutsumura,† Yasuaki Koyama,‡ Yuko Suzuki,‡ Ken-ichi Tominaga,§ Naoshi Yamamoto,†
Tsuyoshi Saitoh,† Yasuyuki Nagumo,† and Hiroshi Nagase*,†,‡
†International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki
305-8575, Japan
‡Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan
§National Institute of Advanced Industrial Science and Technology (AIST), Central 5 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565,
Japan
S
* Supporting Information
ABSTRACT: The aldol condensation of naltrexone with
various aryl aldehydes gives the corresponding 7-benzylidene-
naltrexone derivatives in high yields. However, novel C-ring-
contracted morphinan compounds were produced when 2-
pyridinecarboxaldehyde or its related analogues were used as a
coupling partner. The key structural feature was the existence
of the tetrahydrofuran ring (4,5-epoxy ring, E-ring) of the
morphinan skeleton. The time-resolved in situ IR spectroscopy
of the reaction system indicated the short-lived absorption of
the distorted cyclopropanone intermediate.
Scheme 1. Reaction of 1·HCl with Benzaldehyde (1) and
Reaction of 1·HCl with 2-Pyridinecarboxaldehyde (2)
orphinan alkaloids, such as morphine and codeine, are
pharmacologically important compounds and are widely
M
known to express a variety of pharmacological actions
(analgesia, addiction, antitussive, etc.) by acting on μ, δ, and
κ opioid receptors (MOR, DOR, and KOR).1 For the past
quarter century, we have utilized a commercially available MOR
antagonist, naltrexone (1), as a synthetic template to create
many bioactive compounds.2 For example, we recently reported
that a DOR antagonist, 7-benzylidenenaltrexone (BNTX, 2a)
and its derivatives 2, which were easily synthesized from 1·
hydrochloride (1·HCl), showed both chloroquine-resistance
reversing activity for Plasmodium chabaudi3 and antitrichomo-
nal activity for Trichomonas vaginalis.4 In these investigations,
we discovered that the condensation of 1·HCl with a 2-
pyridinecarboxaldehyde unit led to an unprecedented Favorskii-
type rearrangement reaction. Herein, we describe these results
in detail.
Recently, we reported the efficient synthesis of the BNTX
derivatives 2 by the aldol condensation of 1·HCl with aryl
aldehyde (Scheme 1, eq 1).4a On the other hand, the reaction
of 1·HCl with 2-pyridinecarboxaldehyde afforded the abnormal
C-ring-contracted morphinan compounds 3b, 4b, and 5b under
the same conditions, although the desired compound 2b was
not detected (Scheme 1, eq 2). The structures of 4b and 5b
were determined by 2D NMR (HSQC, HMBC, COSY, and
NOESY), and the stereochemistry of 4b was also confirmed
from X-ray crystallography of 4b (see Figure S1 and Table S2).
Intriguingly, when 3- or 4-pyridinecarboxaldehydes were used
as the coupling partner, this unprecedented reaction did not
progress and afforded the corresponding compounds 2 in high
yields. The reaction of the salt-free 1 also gave the C-ring-
contracted 3b−5b (see Table S1). To the best our knowledge,
there have been no reports regarding such C-ring contraction
with the abnormal rearrangement on the morphinan skeletons.
The commercially available 1·HCl is one of the most useful
synthetic templates to create bioactive morphinan alkaloids,
and thus, we next examined a series of the reaction conditions
to understand the details (Table 1).
Received: January 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Scope of the Reaction Conditions
Table 2. Scope of the Reactant and Morphinan Substrates
yields (%)
x
temp
(°C)
entry (equiv)
base
time
2b
3b
4b
5b
a
1
2
3
4
5
6
7
8
2.1
2.1
piperidine
Et3N
120
3 h
2 d
17 h
3 h
8 h
7 d
3 h
3 h
51
29
20
18
86
72
18
5
22
28
41
41
8
5
4
8
9
a
120
a
2.1
DBU
120
a
2.1
NaOMe
piperidine
piperidine
piperidine
piperidine
120
a
1.1
120
1.1
rt
19
57
10
a
10.0
10.0
120
15
b
a
120
54
a
b
a
In sealed tube. 0.1 equiv of piperidine was used.
CPM = cyclopropylmethyl.
Scheme 2. Reaction of 9 without the E-Ring and Reaction of
1·HCl in CH3CN
The C-ring contraction reaction of 1 proceeded by using not
only piperidine, but also other bases, such as triethylamine, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), or sodium methoxide,
though not with equal selectivity of the products (Table 1,
entries 1−4). When 1.1 equiv of 2-pyridinecarboxaldehyde was
used, the yield of the methyl ester 3b was increased at any
temperature (Table 1, entries 5 and 6). On the contrary, the
spiro-γ-lactones 4b and 5b were preferentially generated when
10.0 equiv of the aldehyde was used (Table 1, entry 7).
Interestingly, when 10.0 equiv of the aldehyde and catalytic
amounts of piperidine were used, the BNTX derivative 2b was
first identified in 54% yield (Table 1, entry 8). The isolation of
2b may have been caused by use of a larger excess of 2-
pyridinecarboxaldehyde to trap piperidine, which is an essential
base for the progress of the C-ring contraction reaction.
Next, we investigated the essential structural moieties in 1
and the aryl aldehyde for the reaction by using the condition of
entry 1 in Table 1 (Table 2 and Scheme 2). As for the aryl
aldehyde as a coupling partner, the 2-pyridinecarboxaldehyde
moiety would be essential for the C-ring contraction (Table 2,
entries 1 and 2, also see Table S1 for comparison). With respect
to the 4,5-epoxymorphinan moiety, the 3-hydroxy group was
not needed for the rearrangement because the 3-O-methylnal-
trexone (6)5 was converted to the respective products 3e−5e,
although the total ratio of the spiro-γ-lactones 4e and 5e was
increased (Table 2, entry 3, vs Table 1, entry 1). In addition,
the compound 76 without a 14-hydroxy group and the
compound 8 having a 17-N-benzyl group also afforded the
C-ring-contracted 3f−5f and 3g−5g, respectively (Table 2,
entries 4 and 5). On the other hand, it was noteworthy that the
reaction of the morphinan 97 lacking the tetrahydrofuran-ring
(4,5-epoxy-ring, E-ring) with the aldehyde afforded the BNTX
derivative 2h (26%) and the structural isomer 2i (35%) with
slow reaction rates, and no C-ring-contracted compound was
detected (Scheme 2, eq 1). This result suggested that the E-ring
in the 4,5-epoxymorphinan structure could be essential for the
C-ring contraction reaction. Moreover, the reaction of 1·HCl
with the aldehyde in acetonitrile was attempted because it
seemed that the source of the methoxy group in the methyl
ester of the compounds 3 would be the solvent (methanol). As
a result, a bicyclo[2.2.1]lactone 10 was obtained as a major
product together with a C-ring-contracted morphinan 11,
which was produced by the reaction of 10 with piperidine, and
4b (Scheme 2, eq 2).
The proposed reaction mechanism for the formation of the
C-ring-contracted morphinans 3−5 and 10 is illustrated in
Scheme 3. The aldol condensation of 1 with 2-pyridinecarbox-
aldehyde in methanol produces the BNTX derivative 2b as the
first intermediate of this reaction. Then, 2b is transformed to a
cyclopropanone intermediate B through an enolate anion A,
which is stabilized owing to the presence of the nitrogen of the
pyridine moiety. The Favorskii-type rearrangement would take
place in the presence of even a weak base because the
neighboring oxygen atom of the E-ring and the ring strain of
the C-ring8 could enhance the acidity of the hydrogen at the C5
position (1H NMR, 4.68 ppm). The reaction of B with another
molecule of 2-pyridinecarboxaldehyde leads to the spiro-γ-
lactones 4b and/or 5b through an intermediate C. In addition,
a relatively stable cyclopropanone D generated by a
B
DOI: 10.1021/acs.orglett.8b00288
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Scheme 3. Possible Mechanism for the Formation of 3b−5b
and 10
Scheme 5. Reaction of 2b in MeOH (0.6 M) at Room
Temperature
protonation of B reacts with methanol to afford the methyl
ester 3b. When the reaction is carried out in acetonitrile, the
intramolecular nucleophilic attack of the hydroxy group at the
C14 position on the carbonyl group occurs to give the
bicyclo[2.2.1]lactone 10.
To confirm the proposed mechanism, we investigated the
reactivity of the presumptive intermediate 2b, which was
synthesized under the conditions of entry 8 of Table 1 (Scheme
4). The reaction of 2b with 1.0 equiv of piperidine in methanol
Figure 1. ReactIR spectra of the reaction of 2b with piperidine in
MeOH at room temperature.
Scheme 4. Investigation of Reactivity of 2b
added to a solution of 2b (1686 cm−1) in methanol (0.6 M) at
room temperature.9 Those IR absorption regions of 3b and 10
were increased over time, whereas the α,β-unsaturated ketone
stretch of 2b was decreased. It should be noted that the
distinguishing small peaks (1832, 1848, and 1874 cm−1), which
would correspond to the reported cyclopropanone absorp-
tion,10 were always identified during the reaction (also see
Figure S2). Additionally, we also carried out DFT calculations
at the B3LYP/6-31+G* level of theory11 for the hypothetical
intermediate D to support the validity of the IR absorption of
the cyclopropanone moiety on the 5-membered C-ring of these
morphinan structures, such as B, C, or D, as shown in Scheme
3. As a result, the calculations indicated that the estimates of the
carbonyl absorption of the intermediate D ranged from 1833 to
1856 cm−1; that is, the theoretical IR values were close to the
actual measured values (see Tables S3 and S4). These results
support the idea that 2b derived from 1 was transformed into
the C-ring-contracted morphinans through the Favorskii-type
rearrangement.
We also performed opioid receptor binding assays for novel
morphinan derivatives 3b and 4b because the BNTX
derivatives 2 have been previously reported to have the higher
affinity for the δ opioid receptor (DOR) than the μ and κ
opioid receptors (MOR and KOR).4b,12 The resulting binding
assay showed that the methyl ester 3b possessed a relatively
higher affinity for the KOR (MOR: Ki = 1.49 nM, DOR: Ki =
1.94 nM, KOR: Ki = 0.795 nM). On the other hand, the spiro-
γ-lactone 4b possessed quite a higher affinity for the DOR
(MOR: Ki = 446 nM, DOR: Ki = 18.4 nM, KOR: Ki = 567
nM). These assays of the C-ring-contracted morphinans
derived from the MOR antagonist 1 inspired us to obtain
more potent and selective DOR and KOR ligands with the
novel skeletons. We will report the details in the near future.
afforded only the methyl ester 3b in high yield. Moreover, we
also identified that the above reaction condition with 2-
pyridinecarboxaldehyde afforded both the methyl ester 3b and
the spiro-γ-lactones 4b and 5b. Furthermore, as we expected,
the reaction of 2b with 4-nitrobenzaldehyde afforded the
corresponding lactones 4j and 5j together with 3b. These
experimental results support the idea that the BNTX derivative
2b was certainly the first reaction intermediate, while a variety
of the spiro-γ-lactones derivatives 4 and 5 could be synthesized
with ease by using this approach.
More supportive mechanistic information was also gained by
using the time-resolved in situ IR spectroscopy (ReactIR) of
the reaction progress. As shown in Scheme 5 and Figure 1, the
methyl ester 3b (1728 cm−1) and the bicyclo[2.2.1]lactone 10
(1789 cm−1) were produced when piperidine (1.0 equiv) was
C
DOI: 10.1021/acs.orglett.8b00288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Ohrui, S.; Okada, T.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.;
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In conclusion, we first discovered that the Favorskii-type
rearrangement of 4,5-epoxymorphinan compounds occurred to
produce the novel C-ring contracted morphinan skeletons by
using 2-pyridinecarboxaldehyde or its related analogs. The
reaction mechanism was supported by the isolation of the first
intermediate 2b, the experimental confirmation of the reactivity
of 2b, and the time-resolved in situ IR spectroscopy of the
reaction system.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00288.
1
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Experimental procedures, characterization data, H and
13C NMR spectra of all new compounds, and DFT
calculations (PDF)
Accession Codes
CCDC 1817651 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
(9) The ReactIR analysis (Figure 1) and the confirmatory experiment
(Scheme 5) were carried out in high concentration (0.6 M) at room
temperature; hence, the bicyclo[2.2.1]lactone 10 was also produced,
unlike in the case of Scheme 4.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nagase.hiroshi.gt@u.tsukuba.ac.jp.
ORCID
Noriki Kutsumura: 0000-0002-1494-2133
Ken-ichi Tominaga: 0000-0002-6078-2169
Hiroshi Nagase: 0000-0003-0428-3979
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI (Grant-in-Aid for
Young Scientists (B)) Grant Number 15K16553 (N.K.),
17K13259 (N.K.), and TORAY Industries, Inc. We thank Dr.
S. Hirayama and Dr. H. Fujii (Kitasato University) for
supporting the study on opioid receptor binding. We thank
Dr. T. Matsumoto (Rigaku Corporation) for support of the X-
ray crystallographic analysis.
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DOI: 10.1021/acs.orglett.8b00288
Org. Lett. XXXX, XXX, XXX−XXX