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 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 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, and neopeltolide are all significant in their usage of macrocyclic stereocontrol en route to the desired structural targets.
Cladiell-11-ene-3,6,7-triol The cladiellin family of marine natural products feature 9-membered rings. The synthesis of (−)-cladiella-6,11-dien-3-ol allowed access to a variety of other members of the cladiellin family. The conversion to cladiell-11-ene-3,6,7-triol makes use of macrocyclic stereocontrol in the dihydroxylation of a trisubstituted olefin. Below is shown the synthetic step controlled by the ground state conformation of the macrocycle, allowing stereoselective dihydroxylation without the usage of an asymmetric reagent. This example of substrate controlled addition is an example of the peripheral attack model in which two centers on the molecule are added two at once in a concerted fashion.
(±)-Periplanone B The synthesis of (±)-periplanone B is a prominent example of macrocyclic stereocontrol. Periplanone B is a sex pheromone of the American female cockroach, and has been the target of several synthetic attempts. Significantly, two reactions on the macrocyclic precursor to (±)-periplanone B were directed using only ground state conformational preferences and the peripheral attack model. Reacting from the most stable boat-chair-boat conformation, asymmetric epoxidation of the cis-internal olefin can be achieved without using a reagent-controlled epoxidation method or a directed epoxidation with an allylic alcohol.
Epoxidation of the ketone was achieved, and can be modeled by peripheral attack of the sulfur ylide on the carbonyl group in a Johnson-Corey-Chaykovsky reaction to yield the protected form of (±)-periplanone B. Deprotection of the alcohol followed by oxidation yielded the desired natural product.
Eucannabinolide In the synthesis of the cytotoxic germacranolide sesquiterpene eucannabinolide, Still demonstrates the application of the peripheral attack model to the reduction of a ketone to set a new stereocenter using NaBH4. Significantly, the synthesis of eucannabinolide relied on the usage of molecular mechanics (MM2) computational modeling to predict the lowest energy conformation of the macrocycle to design substrate-controlled stereochemical reactions.
Neopeltolide Neopeltolide was originally isolated from sponges near the Jamaican coast and exhibits nanomolar cytoxic activity against several lines of cancer cells. The synthesis of the neopeltolide macrocyclic core displays a hydrogenation controlled by the ground state conformation of the macrocycle. ==Occurrence and applications==