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Recent Advances in the Synthesis of Morphine and Related Alkaloids Read chapter Read first chapter

2011 | OriginalPaper | Chapter

Synthesis of Novel Basic Skeletons Derived from Naltrexone

Authors : Hiroshi Nagase, Hideaki Fujii

Published in: Chemistry of Opioids

Publisher: Springer Berlin Heidelberg

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Abstract

We will describe eight interesting reactions using naltrexone derivatives. Almost all these reactions are characteristic of naltrexone derivatives, and can lead to the synthesis of many novel skeletons that provide new interesting pharmacological data. Some of the new reactions that were found with naltrexone derivatives were expanded into general reactions. For example, the reaction of 6α-hydroxyaldehyde derived from naltrexone led to the oxazoline dimer and the 1,3,5-trioxazatriquinane skeleton (triplet drug); this reaction was applied to general ketones which were converted to α-hydroxyaldehydes, followed by conversion to dimers and trimers, as described in Sect. 7.

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Footnotes
1
Although morphine is a classical μ opioid receptor agonist, its intrinsic activity is known to be lower than that of a representative full μ opioid receptor agonist, DAMGO. Moreover, recent reports showed that morphine was a partial agonist for the opioid μ receptor in some pharmacological assays. See [34‐38].
 
2
The thermal decarboxylation of a β-lactone has been widely used for preparation of an olefin. See [51, 52]. Recent examples of the thermal decarboxylation of β-lactones are described in [53‐57].
 
3
Olefins have been prepared by elimination reactions, in which oxazolidinone functioned as a leaving group. See [59‐61].
 
4
In cyclic systems, the extent of anti and syn elimination depends on ring size. Cyclohexyl systems have a very strong preference for anti elimination. See [62, 63].
 
5
The reaction of 58a with the CPM group seemed to proceed most rapidly. This observation might be explained by considering the very stable cyclopropylcabinyl cation (see Sect. 4 and [39‐42]).
 
6
For X-ray crystallography of nonconjugated iminium salts, see [69‐71].
 
7
For X-ray crystallography of conjugated iminium salts, see [72‐82].
 
8
The NBO analysis showed that the optimal bond length of C6–C7 was also 0.007 Å longer than that of the corresponding bond in 68c, with an interaction energy between σ (C6–C7) and π* (N1–C23) of 4.98 kcal/mol. However, in X-ray crystallography, the C6–C7 in 63b showed the same bond length (1.551 Å) as the C13–C12 in 68c. This result suggested that the C5–C6 might also partially participate in the stabilization of the iminium ion.
 
9
In the case of the Fe(CO)3 complex 64, the reduction was reported to take 20 min (see [84]). On the other hand, the reduction of 63a was completed within 5 min.
 
10
The reaction of the Fe(CO)3 complex 64 with NaCN was reported to proceed in acetone under reflux for 5 min (see [83]). In contrast, the reaction of 63a was completed at room temperature within 5 min.
 
11
The fragmentation of a 7-acyl-6,14-endoethenotetrahydrothebaine derivative was also reported. See [99].
 
12
For synthesis of pentazocine, see [107‐111]. For synthesis of (–)-pentazocine with optical resolution, see [112, 113]. For the asymmetric synthesis of (–)-pentazocine, see the asymmetric synthesis of (–)-metazocine (an N-methyl derivative of (–)-pentazocine) has also been reported, [114]; very recently, the asymmetric synthesis of (–)-9-epi-pentazocine was also reported [115]; it has been shown that (–)-pentazocine is more potent than its antipode [116].
 
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Metadata
Title
Synthesis of Novel Basic Skeletons Derived from Naltrexone
Authors
Hiroshi Nagase
Hideaki Fujii
Copyright Year
2011
Publisher
Springer Berlin Heidelberg
Book
Chemistry of Opioids

Print ISBN: 978-3-642-18106-1

Electronic ISBN: 978-3-642-18107-8

Copyright Year: 2011

DOI
https://doi.org/10.1007/128_2010_75