Tetrahedron Letters
Stereoselective syntheses of 3-dehydroxynaltrexamines and N-methyl-
3-dehydroxynaltrexamines
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Mengchu Li, Celsey M. St. Onge, Yan Zhang
Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E Leigh St, Richmond, VA 23298, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Methodology is presented for the synthesis of 6a/b-3-dehydroxynaltrexamines and 6a/b-N-methyl-3-
dehydroxynaltrexamines. A stereoselective route is provided for each target compound while a novel
Received 8 June 2020
Revised 8 August 2020
Accepted 17 August 2020
Available online 20 August 2020
one-pot method for the synthesis of 6 /b-N-methyl-3-dehydroxynaltrexamines is also explored. These
a
results enable the versatile and efficient preparation of key epoxymorphinan intermediates to facilitate
future selective opioid ligand discovery and development.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
3-Dehydroxynaltrexamines
N-Methyl-3-dehydroxynaltrexamines
Stereoselective synthesis
One-pot method
Introduction
Results and discussion
6
a
- and 6b-Naltrexamines (NTA, Fig. 1) are crucial epoxymor-
As shown in Scheme 1, novel target compounds 4 and 7 were
successfully prepared via asymmetric synthesis. Previously, similar
stereoselective methods have been applied to prepare a/b-naltrex-
phinan intermediates used for the synthesis of opioid receptor
ligands [1–6]. Based on in vitro and in vivo studies, many synthetic
NTA derivatives with selective kappa opioid receptor (KOR) bind-
ing profiles have exhibited potential therapeutic effects for a wide
variety of diseases such as alcohol addiction, cocaine addiction,
pruritus, and anagelsia [1–8]. Many KOR ligands have also shown
high affinity for the mu opioid receptor (MOR) making them
MOR/KOR dual-selective ligands, e.g. nalfurafine (Fig. 1). Recent
structural biology studies [9–12] have provided insight into opioid
receptor subtype selective molecular design. For example, the 3-
hydroxy group in the epoxymorphinan skeleton may be essential
for MOR binding but not for KOR binding, as exemplified by 42B
(Fig. 1). It is therefore conceivable that the corresponding 3-dehy-
droxy counterparts of NTA will be of cardinal significance in the
preparation of KOR-selective molecules. Nonetheless, no prepara-
amines [14,15]. In detail, the starting material 3-dehydroxynal-
trexone 1 was first prepared from naltrexone (Scheme S1). Then,
the iminium ion intermediate 2 was formed by the azeotropic
removal of water to allow nucleophilic addition. Without any
purification process, the N-dibenzyl protected 6b-3-dehydrox-
yamine 3 was obtained through reductive amination of intermedi-
ate 2. As previously reported [14], the cyclohexyl C ring in 2 may
shift from the more stable chair conformation to a higher energy
boat conformation due to the strain between the epoxy ether oxy-
gen and the benzyl group in the chair conformation (Fig. 2). Thus,
the reducing agent would mostly approach the C ring from the
more sterically accessible
a-face to yield a b-amine after hydride
transfer, therefore achieving stereoselectivity. The fact that 6
a-epi-
tory method for either 6
been reported, nor their N-methyl derivatives.
Herein we present, for the first time, stereoselective synthetic
strategies for 3-dehydroxynaltrexamines and N-methyl-3-dehy-
droxynaltrexamines as essential building blocks for the prepara-
tion of opioid ligands [12,13].
a
- or 6b-3-dehydroxynaltrexamine has
mer products were not observed further supports this mechanism.
Additionally, we believe the repulsion between the epoxy ether
oxygen and the iminium ion is also an important driving force in
the chair-to-boat conformation change. Following this critical step,
debenzylation of intermediate 3 gave the desired 6b-3-dehydrox-
ynaltrexamine 4 as its hydrochloride salt in acceptable yield.
Meanwhile, the key intermediate 6 used to prepare 6a-3-dehy-
droxynaltrexamine was obtained through imine formation and
stereoselective reduction, followed by catalytic hydrogenation to
give 7. Of note, intermediate 6 was an imine rather than an imi-
nium ion due to the less acidic conditions (absence of benzoic
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Corresponding author.
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