Synthesis of Tetrahydroisoquinoline and Protoberberine Derivatives
A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".
Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 12194
Special Issue Editor
Interests: designing new methods for the synthesis of non-racemic tertiary amines and systems for further transformation into alkaloids; asymmetric synthesis of tetrahydroisoquinoline and protoberberine derivatives; Petasis reaction
Special Issue Information
Dear Colleagues,
Tetrahydroisoquinoline (THIQ) derivatives, including isoquinoline alkaloids, belong to optically active amines. Isoquinoline alkaloids are the most common group of alkaloids in nature. Most of them possess at least one stereogenic centre in the molecule and occur naturally in enantiomerically pure forms. There is a strong connection between biological activity and the configuration of a stereogenic centre, hence the necessity of searching for new methods for the asymmetric synthesis of compounds with specified, given configurations. Biological activity depends on interactions between chiral compounds and receptors; the latter recognize only one of two enantiomers. In the case of pharmaceuticals, very often, only one enantiomer has therapeutic properties, whereas the other one can be less effective for an organism (the best case) or a poison (the worst case). A few examples of these derivatives are as follows. Morphine possesses remarkable analgesic activity. Ecteinascidin 743 exhibits activity against the proliferation of a wide range of cancer subtypes at low concentrations, and was approved by the US FDA for the treatment of liposarcoma and leiomyosarcoma. Psychotrine has been used as an inhibitor of HIV-1. Lycorine also shows potential in anti-cancer studies. Chiral tetrahydroisoquinolines are universal structural units in a large number of biologically active molecules, including natural alkaloids and pharmaceuticals. For instance, chiral 1-substituted THIQ motifs are present in (+)-cryptostyline II, the drug molecule solifenacin, and an AMPA receptor antagonist. Due to their significance, extensive efforts have been devoted to the development of highly efficient methods for producing chiral THIQ.
Protoberberines belong to another important group of isoquinoline alkaloids, characterized by a tetracyclic ring skeleton and an isoquinoline core. Various alkoxy (methoxy and methylenedioxy) substitution patterns are found in rings A and D at the carbon atoms numbered C-2, 3, 9 and 10. An example is a molecule of tetrahydropalmatine isolated from Corydalis cava. Another substitution pattern at the carbon atoms numbered C-2, 3, 10 and 11 occurs in the xylopinine molecule isolated from Xylopia discreta. The stereogenic center is present at C-13a. Protoberberines have been used in traditional medicine in China and other Asian countries because of their diverse biological activities. The anti-inflammatory, antimicrobial, antileukemic and antitumor properties of these alkaloids have led to considerable efforts towards the development of their synthetic analogs.
Recent methods for the asymmetric synthesis of isoquinoline alkaloids have generally been based on two synthetic strategies:
- The stereochemical modification of the traditional, classical methods of the synthesis of the tetrahydroisoquinoline system:
- Sequential Bischler–Napieralski cyclizaton/reduction;
- Pictet–Spengler cyclization;
- Various Pomeranz–Fritsch cyclizations.
- The so-called C1-Cα connectivity approach: the introduction of electrophilic or nucleophilic carbon units into the C-1 position of an isoquinoline derivative:
- Meyer’s formamidine methodology, for example;
- The addition of carbon nucleophiles to imines.
Thus, a new stereogenic center is created at an early step of the synthesis. A great number of naturally occurring isoquinoline alkaloids owe their chirality to the presence of a stereogenic centre at the C-1 carbon (or C-13a in protoberberines), and the development of methodologies for accessing this center while maintaining configurational integrity has been a subject of great interest.
It is a pleasure to invite you to submit a manuscript to this Special Issue.
Assoc. Prof. Dr. Maria Chrzanowska
Guest Editor
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Keywords
- Tetrahydroisoquinoline
- Protoberberine
- Alkaloid derivative
- Total synthesis
- Asymmetric synthesis
