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Название: Spiro Compounds
Автор: Группа авторов
Издательство: John Wiley & Sons Limited
Жанр: Химия
isbn: 9781119567653
isbn:
1.1 Notes on IUPAC Rules for Spiro Compounds
Naming spirocycles could be quite complex. The accepted rules are collected in the IUPAC blue book [1, 19].
Simplifying with two examples, the structure 26 is numbered starting from the smallest cycle (Figure 1.10). The name comes from the prefix spiro followed by square brackets containing the number of atoms of the two cycles starting from the smallest and excluding the spirocenter. In this case, the functional group is an alkane so that the name became spiro[4,5]decane.
Figure 1.11 Example of naming chiral spiro compounds.
When the compound is chiral because it contains a chiral center, the CIP rules are followed. In the case in which the substituents on the spirocenter are the same, but the structures display an axial chirality as in Figure 1.11, we assign arbitrarily the priority to one of the cycles and then, within each cycle the order follows the CIP rules: a>a′>b>b′.
References
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2 Selected Applications of Spirocycles in Medicinal Chemistry
Matthias Baud
School of Chemistry and Institute for Life Sciences, University of Southampton, Southampton, UK
2.1 Introduction
Spiro compounds contain two rings, connected by a single sp3 hybridized quaternary center, the “spiroatom” [1]. The latter is often a carbon, although a number of quaternary N‐spiro ammoniums have also been reported. Trospium chloride (1) (Table 2.1) is a good example, and its spiro ammonium motif can be readily prepared by double N‐alkylation of endo‐nortropine [3]. Spirocyclic systems are found in a wide range of natural products [4], including spiro‐ketals [5, 6], lactones [7], lactams [8, 9], and oxindoles [10–12]. An early and illustrative example of spirocyclic natural product which has attracted the attention of medicinal chemists is the antibiotic platensimycin (2). It is a metabolite from Streptomyces platensis which represents a structurally unusual example of bioactive molecule containing a carbaspirocyclic scaffold. Its antibiotic activity was reported by Merck in 2006, as part of a screening campaign to identify inhibitors of beta‐ketoacyl synthases I/II (FabF/B) enzymes [13]. Inhibition of FAB enzymes by platensimycin leads to impaired biosynthesis of key fatty acids required bacterial cell membrane integrity [14]. Platensimycin displays activity against a range of Gram‐positive bacteria, including strains showing resistance to other potent antibiotics such as methicillin, vancomycin, linezolid, or macrolide. Structural studies on an Escherichia coli FabF(C163Q) in complex with platensimycin highlighted important interactions underlying complex formation. The shape complementarity and conformational restriction provided by the spiro motif are important contributors to the potency of platensimycin, allowing polar interactions and hydrophobic contacts at the binding site entrance (Figure 2.1) [13]. The first total synthesis of racemic platensimycin was reported by Nicolaou on the same year (Scheme 2.1) [15], involving a key ruthenium‐catalyzed enyne cycloisomerization [16]. Since then, stereoselective syntheses of platensimycin spirocyclic core based on rhodium‐catalyzed asymmetric cycloisomerization and hypervalent iodine‐mediated de‐aromatizing cyclization [17], decarboxylative allylation [18], and intramolecular Diels–Alder [19] have been reported.
Table 2.1 Selected examples of FDA‐ approved drugs containing spirocyclic motifs.
Source: Adapted from Knox et al. [2].
| Structure | ID | Name (Trade name) | Indication |
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