Macrocycle

class=skin-invert-image|thumb|240px|[[Erythromycin, a macrolide antibiotic, is one of many naturally occurring macrocycles.]]

Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry.

Synthesis

The formation of macrocycles by ring-closure is called macrocyclization. The central challenge to macrocyclization is that few bond-forming reactions give large rings. Instead, medium sized rings or polymers tend to form. Early macrocyclizations were achieved ketonic decarboxylations for the preparation of terpenoid macrocycles. So, while Ružička was able to produce various macrocycles, the yields were low. This kinetic problem can be addressed by using high-dilution reactions, whereby intramolecular processes are favored relative to polymerizations. Reactions amenable to high dilution include Dieckmann condensation and related based-induced reactions of esters with remote halides. High dilution ring-closing metathesis (1mg/1mL solvent) was used to prepare muscone in 76% yield.

:class=skin-invert-image|550px|left|Synthesis of muscone via high dilution RCM

Some macrocyclizations are achieved using template reactions. Templates are ions, molecules, surfaces etc. that bind and pre-organize reactants, guiding them toward formation of a particular ring size. The crown ethers are often generated in the presence of an alkali metal cation, which organizes the condensing components by complexation. An illustrative macrocyclization is the synthesis of (−)-muscone from (+)-citronellal.

class=skin-invert-image|thumb|right|[[Uroporphyrinogen III, biosynthetic precursor to porphyrins.]]

Stereocontrol

Macrocyclic stereocontrol refers to the directed outcome of a given intermolecular or intramolecular reaction that is governed by the conformational preference of a macrocycle. Stereocontrol for cyclohexane rings is well established in organic chemistry, in large part due to the axial/equatorial preferential positioning of substituents on the ring. Macrocyclic stereocontrol models the substitution and reactions of medium and large rings in organic chemistry, with remote stereogenic elements providing enough conformational influence to direct the outcome of a reaction.

Early assumptions towards macrocycles in synthetic chemistry considered them far too floppy to provide any degree of stereochemical or regiochemical control in a reaction. Investigations in the late 1970s and 1980s challenged this assumption, while several others found crystallographic data and NMR data that suggested macrocyclic rings were not the floppy, conformationally ill-defined species many assumed.

The rigidity of a macrocyclic ring depends significantly on the substitution and the overall size. Significantly, even small conformational preferences, such as those envisioned in floppy macrocycles, can profoundly influence the ground state of a given reaction, providing stereocontrol such as in the synthesis of miyakolide.

Reaction classes used in synthesis of natural products under the macrocyclic stereocontrol model for obtaining a desired stereochemistry include: hydrogenations such as in neopeltolide and (±)-methynolide, epoxidations such as in (±)-periplanone B hydroborations such as in 9-dihydroerythronolide B, enolate alkylations such as in (±)-3-deoxyrosaranolide, and reductions such as in eucannabinolide.

Conformational preferences

Macrocycles can access a number of stable conformations, with preferences to reside in those that minimize the number of transannular nonbonded interactions within the ring. Conformational analysis of odd-membered rings suggests they tend to reside in less symmetrical forms with smaller energy differences between stable conformations.

Cyclooctane

thumb|right|class=skin-invert-image|240px

Conformational analysis of medium rings begins with examination of cyclooctane. Spectroscopic methods have determined that cyclooctane possesses three main conformations: chair-boat, chair-chair, and boat-boat. Cyclooctane prefers to reside in a chair-boat conformation, minimizing the number of eclipsing ethane interactions (shown in blue), as well as torsional strain. The chair-chair conformation is the second most abundant conformation at room temperature, with a ratio of 96:4 chair-boat:chair-chair observed. From the cyclooctene figure below, it can be observed that one face is more exposed than the other, foreshadowing a discussion of privileged attack angles (see peripheral attack).

X-ray analysis of functionalized cyclooctanes provided proof of conformational preferences in these medium rings. Significantly, calculated models matched the obtained X-ray data, indicating that computational modeling of these systems could in some cases quite accurately predict conformations. The increased sp2 character of the cyclopropane rings favor them to be placed similarly such that they relieve non-bonded interactions.

Cyclodecane

class=skin-invert-image|right|225px

Similar to cyclooctane, a cyclodecane ring exhibits several conformations with two lower energy conformations. The boat-chair-boat conformation is energetically minimized, while the chair-chair-chair conformation has significant eclipsing interactions.

These ground-state conformational preferences are useful analogies to more highly functionalized macrocyclic ring systems, where local effects can still be governed to first approximation by energy minimized conformations even though the larger ring size allows more conformational flexibility of the entire structure. For example, in methyl cyclodecane, the ring can be expected to adopt the minimized conformation of boat-chair-boat. The figure below shows the energetic penalty between placing the methyl group at certain sites within the boat-chair-boat structure. Unlike canonical small ring systems, the cyclodecane system with the methyl group placed at the "corners" of the structure exhibits no preference for axial vs. equatorial positioning due to the presence of an unavoidable gauche-butane interaction in both conformations. Significantly more intense interactions develop when the methyl group is placed in the axial position at other sites in the boat-chair-boat conformation. The conformational flexibility of larger rings potentially allows for a combination of acyclic and macrocyclic stereocontrol to direct reactions.

The peripheral attack model

Macrocyclic rings containing sp2 centers display a conformational preference for the sp2 centers to avoid transannular nonbonded interactions by orienting perpendicular to the plan of the ring. W. Clark Still proposed that the ground state conformations of macrocyclic rings, containing the energy minimized orientation of the sp2 center, display one face of an olefin outwards from the ring. Addition of reagents from the outside the olefin face and the ring (peripheral attack) is thus favored, while attack from across the ring on the inward diastereoface is disfavored. Ground state conformations dictate the exposed face of the reactive site of the macrocycle, thus both local and distant stereocontrol elements must be considered. The peripheral attack model holds well for several classes of macrocycles, though relies on the assumption that ground state geometries remain unperturbed in the corresponding transition state of the reaction.

Early investigations of macrocyclic stereocontrol studied the alkylation of 8-membered cyclic ketones with varying substitution.

Unlike the cyclooctanone case, alkylation of 2-cyclodecanone rings does not display significant diastereoselectivity. The structure minimizing repulsive steric interactions provides the observed product by having the lowest barrier to a transition state for the reaction. Though no external attack by a reagent occurs, this reaction can be thought of similarly to those modeled with peripheral attack; the lowest energy conformation is the most likely to react for a given reaction.

The lowest energy conformations of macrocycles also influence intramolecular reactions involving transannular bond formation. In the intramolecular Michael addition sequence below, the ground state conformation minimizes transannular interactions by placing the sp2 centers at the appropriate vertices, while also minimizing diaxial interactions.

Prominent examples in synthesis

These principles have been applied in multiple natural product targets containing medium and large rings. The syntheses of cladiell-11-ene-3,6,7-

triol, eucannabinolide,

thumb|right|200px|The potassium (K+) complex of the macrocycle [[18-crown-6 .]]

Macrocycles are often bioactive and could be useful for drug delivery.

Macrocycles in Drug Discovery

Over the last few years, macrocyclic molecules have become increasingly relevant in drug discovery. For a long time, this motif was found almost exclusively in natural products (s. Cyclosporine), but it can now also be found in some completely synthetic molecules (s. Grazoprevir).

Special focus is placed on macrocyclic peptides, as these are comparatively easy to produce. In addition, their risk is classified as comparatively low because, like the body's own proteins, they consist of amino acids (which can, however, be modified). Normally it is difficult for molecules above a certain size and number of hydrogen bond donors and acceptors to get absorbed orally. However, it is now possible to make these molecules bio-orally available through certain modifications of the amino acids and through high N-alkylation. A chameleon-like behaviour of such molecules can also be observed, because the parts of the molecules that are directed outwards and inwards can change depending on the environment and thus influence the solubility.

Subdivisions

Cryptand
Rotaxane
Catenane
Molecular knot

Effective molarity
Macrocyclic stereocontrol