Macrocycle
Early assumptions towards macrocycles in synthetic chemistry considered them far too floppy to provide any degree of stereochemical or regiochemical control in a reaction.
[14][15] 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.
[16] Reaction classes used in synthesis of natural products under the macrocyclic stereocontrol model for obtaining a desired stereochemistry include: hydrogenations such as in neopeltolide [17] and (±)-methynolide,[18] epoxidations such as in (±)-periplanone B[19] and lonomycin A,[20] hydroborations such as in 9-dihydroerythronolide B,[21] enolate alkylations such as in (±)-3-deoxyrosaranolide,[22] dihydroxylations such as in cladiell-11-ene-3,6,7-triol,[23] and reductions such as in eucannabinolide.
Cyclooctane prefers to reside in a chair-boat conformation, minimizing the number of eclipsing ethane interactions (shown in blue), as well as torsional strain.
[11] 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.
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 conjunction with remote substituent effects, local acyclic interactions can also play an important role in determining the outcome of macrocyclic reactions.
[30] The conformational flexibility of larger rings potentially allows for a combination of acyclic and macrocyclic stereocontrol to direct reactions.
Ground state conformations dictate the exposed face of the reactive site of the macrocycle, thus both local and distant stereocontrol elements must be considered.
[11] The proximity of the methyl group to the ester linkage was directly correlated with the diastereomeric ratio of the reaction products, with placement at the 9 position (below) yielding the highest selectivity.
Placement of the methyl group at the 9-position in the axial position yields the most stable ground state conformation of the 10-membered ring leading to high diastereoselectivity.
[32] 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.
[33] The structure minimizing repulsive steric interactions provides the observed product by having the lowest barrier to a transition state for the reaction.
The syntheses of cladiell-11-ene-3,6,7- triol,[23] (±)-periplanone B,[19] eucannabinolide,[24] and neopeltolide[17] are all significant in their usage of macrocyclic stereocontrol en route to the desired structural targets.
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.
Significantly, two reactions on the macrocyclic precursor to (±)-periplanone B were directed using only ground state conformational preferences and the peripheral attack model.
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 was originally isolated from sponges near the Jamaican coast and exhibits nanomolar cytoxic activity against several lines of cancer cells.
