Macrocyclic stereocontrol

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.

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, (±)-periplanone B, eucannabinolide, and neopeltolide are all significant in their usage of macrocyclic stereocontrol en route to obtaining the desired structural targets.

Cladiell-11-ene-3,6,7-triol

The cladiellin family of marine natural products possess interesting molecular architecture, generally containing a 9-membered medium-sized ring. The synthesis of (−)-cladiella-6,11-dien-3-ol allowed access to a variety of other members of the cladiellin family. Notably, 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.

Criticisms

The peripheral attack model is based on predicting lowest energy conformations of an inherently complicated system, where nuanced perturbations can cause huge stereodifferentiating consequences. By modeling peripheral attack using the Curtin-Hammett scenario depicted above, the transition state is excluded from this conformation analysis by assuming that the barrier to each transition state from a given conformation is the same and thus that ground state conformations are the sole product determining factor. A significant criticism is the mapping of medium-sized ring conformations and influences onto larger ring systems. Macrocycles can possess varying degrees of rigidity in their structure, making a single peripheral attack model difficult to apply to all systems. Different classes of reactions might not fit the peripheral attack model, as reactions such as epoxidations, hydroxylations, alkylations, and reductions all proceed through different transition states.