Macrocyclic Stereocontrol
Encyclopedia
Macrocyclic stereocontrol refers to the directed outcome of a given inter or intramolecular reaction on a ring containing 8 or more atoms that is governed by the conformational or geometrical preference of the ring rather than by remote or absolute stereochemical methods. Macrocyclic stereocontrol represents a useful method for controlling the substitution and reactions of medium and large rings in organic chemistry. 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 work of Clark W. Still in the late 1970s and 1980s challenged this assumption experimentally, while several others had found crystallographic data and NMR data suggesting that macrocyclic rings were not the floppy, conformationally ill-defined species many assumed.
interactions (shown in blue). Similarly, of its many conformations, cyclodecane prefers to reside in a boat-chair-boat structure, relieving the eclipsing ethane interactions of the chair-chair-chair conformation.
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. Substitution on these rings can be approximated using parameters similar to those found for smaller rings. For example, in methyl cyclodecane, the ring can be expected to adopt the minimized conformation of boat-chair-boat. The placement of the methyl substituent is key in determining the energy-minimized structure of cyclodecane. The figure below shows the energetic penalty of placing the methyl group at certain sites within the boat-chair-boat structure. Predicted computationally, the pseudo A-value is best treated as approximate energy differences between placing the methyl substituent in the axial and equatorial positions. 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 a gauche-butane interaction in both forms. Significantly more intense interactions develop when the methyl group is placed in the axial position at other sites in the boat-chair-boat conformation.
In larger macrocycles, as the structure increasingly becomes acyclic, it can be inferred that acyclic stereocontrol elements begin to play as significant a role in determining the stereochemical outcome of a reaction as the minimization of transannular interactions. Thus, the elements depicted below begin to play important role in stereochemical outcomes of macrocyclic reactions.
Early investigations of macrocyclic stereocontrol investigated the alkylation of 8-membered cyclic ketones with varying substitution. In the example below, alkylation of 2-methylcyclooctanone occurred to yield the predominantly trans product. Proceeding from the lowest energy conformation of 2-methylcycloctanone, peripheral attack is observed from either one of the low energy (energetic difference of 0.5 (kcal/mol)) enolate conformations, resulting in a trans product from either of the two depicted transition state conformations.
Conjugate addition to the E-enone below related also follows the expected peripheral attack model to yield predominantly trans product. High selectivity in this addition can be attributed to the placement of sp2 centers such that transannular nonbonded interactions are minimized, while also placing the methyl substitution in the more energetically favorable position for cyclodecane rings. This ground state conformation heavily biases conjugate addition to the less hindered diastereoface.
Conformational Preferences
Macrocycles can have access to a number of stable conformations, with preference to reside in those which minimize the number of transannular nonbonded interactions within the ring. Analysis of the factors important in considering larger macrocyclic conformations can be modeled by looking at medium ring conformations (8-10 atoms). Cyclooctane prefers to reside in a chair-boat conformation, minimizing the number of eclipsing ethaneEthane
Ethane is a chemical compound with chemical formula C2H6. It is the only two-carbon alkane that is an aliphatic hydrocarbon. At standard temperature and pressure, ethane is a colorless, odorless gas....
interactions (shown in blue). Similarly, of its many conformations, cyclodecane prefers to reside in a boat-chair-boat structure, relieving the eclipsing ethane interactions of the chair-chair-chair conformation.
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. Substitution on these rings can be approximated using parameters similar to those found for smaller rings. For example, in methyl cyclodecane, the ring can be expected to adopt the minimized conformation of boat-chair-boat. The placement of the methyl substituent is key in determining the energy-minimized structure of cyclodecane. The figure below shows the energetic penalty of placing the methyl group at certain sites within the boat-chair-boat structure. Predicted computationally, the pseudo A-value is best treated as approximate energy differences between placing the methyl substituent in the axial and equatorial positions. 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 a gauche-butane interaction in both forms. Significantly more intense interactions develop when the methyl group is placed in the axial position at other sites in the boat-chair-boat conformation.
In larger macrocycles, as the structure increasingly becomes acyclic, it can be inferred that acyclic stereocontrol elements begin to play as significant a role in determining the stereochemical outcome of a reaction as the minimization of transannular interactions. Thus, the elements depicted below begin to play important role in stereochemical outcomes of macrocyclic reactions.
Reactivity and Conformational Preferences
The stereochemical result of a given reaction on a macrocycle capable of adopting several conformations can be modeled by the Curtin-Hammett scenario where two ground state conformations exist in a rapid equilibrium, though with some difference in their ground state energies. In the scenario modeled below, conformation B is lower in energy than conformation A, and also possesses a lower energy barrier to its transition state in a hypothetical reaction, thus the product formed is predominantly product B (P B) arising from conformation B via transition state B (TS B). The inherent preference of a ring to exist in one conformation over another provides a tool for stereoselective control of reactions by biasing the ring and its substitution into a given configuration in the ground state. The energy differences, ΔΔG‡ and ΔG0 are significant considerations in this scenario. The preference for one conformation over another can be characterized by ΔG0, the free energy difference which can at some level be analyzed by conformational analysis. The free energy difference between the two transition states of each conformation on its path to product formation is given by ΔΔG‡.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. Clark W. 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. The peripheral attack model holds well for several classes of macrocycles.Early investigations of macrocyclic stereocontrol investigated the alkylation of 8-membered cyclic ketones with varying substitution. In the example below, alkylation of 2-methylcyclooctanone occurred to yield the predominantly trans product. Proceeding from the lowest energy conformation of 2-methylcycloctanone, peripheral attack is observed from either one of the low energy (energetic difference of 0.5 (kcal/mol)) enolate conformations, resulting in a trans product from either of the two depicted transition state conformations.
Conjugate addition to the E-enone below related also follows the expected peripheral attack model to yield predominantly trans product. High selectivity in this addition can be attributed to the placement of sp2 centers such that transannular nonbonded interactions are minimized, while also placing the methyl substitution in the more energetically favorable position for cyclodecane rings. This ground state conformation heavily biases conjugate addition to the less hindered diastereoface.
Prominent Examples in Synthesis
These principles have been applied in multiple natural product targets containing medium and large rings. The syntheses of Maytansine, (±)-3-Deoxyrosaranolide, and (±)-Periplanone B are all significant in their usage of macrocyclic stereocontrol to obtain the desired structural targets.See also
- Asymmetric inductionAsymmetric inductionAsymmetric induction in stereochemistry describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment...
- Conformational isomerismConformational isomerismIn chemistry, conformational isomerism is a form of stereoisomerism in which the isomers can be interconverted exclusively by rotations about formally single bonds...
- Curtin-Hammett principleCurtin-Hammett principleThe Curtin–Hammett principle is a principle in chemical kinetics proposed by David Yarrow Curtin and Louis Plack Hammett. It states that, for a reaction that has a pair of reactive intermediates or reactants that interconvert rapidly , each going irreversibly to a different product, the product...