Strained cyclophane natural products: Macrocyclization at its limits

Abstract

Cyclophane natural products comprise an intriguing class of structurally diverse compounds. As inherent for all cyclic compounds regardless of their origin, macrocyclization is naturally the most decisive step, which defines the overall efficiency of the synthetic pathway. Especially in small cyclophane molecules, this key step constitutes an even greater challenge. Due to the strain imparted by the macrocyclic system, free rotation of the benzene ring(s) is often restricted depending on both the constitution of the tether and the aromatic portions. Not surprisingly, the synthesis of natural cyclophanes with their often outstanding pharmaceutical activities and the inherent issues associated with their preparation has attracted much attention among the synthetic community. In particular, it stimulated the development of new strategies for the ring-closing step, as often otherwise well established and robust reactions fail to perform effectively. In this review, we describe the challenges synthetic chemists are facing during the synthesis of this small, but structurally and biologically fascinating class of natural products, concentrating on the representatives exhibiting configurational stability. The main focus will be on the different concepts for the installation of the macrocyclic system, in most cases the central problem in assembling these extremely rigid molecules.

A twist of nature – the significance of atropisomers in biological systems

“…The discovery of Haouamine A (Figure 14, Compound 64) from a species of ascidian (sea squirt) 104 provided a unique molecular structure following extensive NMR analysis and X-ray crystallography. This structure contained a p-cyclophane moiety, a biaryl axis with a relatively unique, highly strained 'bent' benzene ring, 105 and a spiro fused-ring system. The originally isolated molecule was observed to contain two rapidly-interconverting isomers; the cause for this was thought to be the result of either a slowed pyramidal inversion of the sp 3 nitrogen, or the presence of an atropisomer (Figure 14, compound 19).…”

Efficient and Modular Synthesis of New Structurally Diverse Functionalized [n]Paracyclophanes by a Ring‐Distortion Strategy

“…[4] These challenging reactions often require high dilution conditions and/or conformational control elements to facilitate ring-closure. [2][3][4][5] Strategies enabling the formation of [n]paracyclophanes from acyclic precursors by construction of the aromatic ring are also appealing. [6][7][8][9] In this context, cobalt-and rhodium-catalyzed [2+2+2]-cycloadditions of a,w-diynes with alkynes have been developed, but the challenge is to control the regioselectivity by an appropriate selection of substrates.…”

“…[1] Despite their inherent strain, [n]paracyclophanes, and especially those incorporating an aryl ether, are encountered in many bioactive natural products [2] as well as in synthetic protease inhibitors.…”

Observations on the Influence of Precursor Conformations on Macrocyclization Reactions

“…5 Macrocyclic peptides and peptidomimetics are a sub-class of macrocycles, the synthesis 6 and easy of cyclization 7,8 of which have been topics of excellent recent papers. The macrocyclization chemistry of particular challenging cyclophane natural products has similarly been highlighted 9 and the efficiency of such reactions in terms of the relation between chemical yield and concentration was also addressed lately. 10 In order to harvest the potential of macrocycles for screening campaigns, one has to face the challenges posed by this compound class: the chemistry of cyclization is also the chemistry of oligomerization, which often compels that high dilution conditions are employed.…”