Macrocyclic stereocontrol refers to the directed outcome of a given intermolecular or intramolecular chemical reaction, generally an organic reaction, that is governed by the conformational or geometrical preference of a carbocyclic or heterocyclic ring, where the ring containing 8 or more atoms.
Introduction
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. The experiments of W. Clark Still 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 degree to which a macrocyclic ring is either rigid or floppy depends significantly on the substitution of the ring 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. Computational modeling can predict conformations of medium rings with reasonable accuracy, as Still used molecular mechanics modeling computations to predict ring conformations to determine potential reactivity and stereochemical outcomes.
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 and lonomycin A, hydroborations such as in 9-dihydroerythronolide B, enolate alkylations such as in (±)-3-deoxyrosaranolide, dihydroxylations such as in cladiell-11-ene-3,6,7-triol, 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. Medium rings (8-11 atoms) are the most strained with between 9-13 (kcal/mol) strain energy; analysis of the factors important in considering larger macrocyclic conformations can thus be modeled by looking at medium ring conformations. Conformational analysis of odd-membered rings suggests they tend to reside in less symmetrical forms with smaller energy differences between stable conformations.
Cyclooctane
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.
Substitution positional preferences in the ground state conformer of methyl cyclooctane can be approximated using parameters similar to those for smaller rings. In general, the substituents exhibit preferences for equatorial placement, except for the lowest energy structure (pseudo A-value of -0.3 kcal/mol in figure below) in which axial substitution is favored. The "pseudo A-value" is best treated as the approximate energy difference between placing the methyl substituent in the equatorial or axial positions. The most energetically unfavorable interaction involves axial substitution at the vertex of the boat portion of the ring (6.1 kcal/mol).
These energetic differences can help rationalize the lowest energy conformations of 8 atom ring structures containing an sp2 center. In these structures, the chair-boat is the ground state model, with substitution forcing the structure to adopt a conformation such that non-bonded interactions are minimized from the parent structure. 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).