Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry.
Synthesis The formation of macrocycles by ring-closure is called macrocyclization. The central challenge to macrocyclization is that few bond-forming reactions give large rings. Instead, medium sized rings or polymers tend to form. Early macrocyclizations were achieved ketonic decarboxylations for the preparation of terpenoid macrocycles. So, while Ružička was able to produce various macrocycles, the yields were low. This kinetic problem can be addressed by using high-dilution reactions, whereby intramolecular processes are favored relative to polymerizations. Reactions amenable to high dilution include Dieckmann condensation and related based-induced reactions of esters with remote halides. High dilution ring-closing metathesis (1mg/1mL solvent) was used to prepare muscone in 76% yield.
Some macrocyclizations are achieved using template reactions. Templates are ions, molecules, surfaces etc. that bind and pre-organize reactants, guiding them toward formation of a particular ring size. The crown ethers are often generated in the presence of an alkali metal cation, which organizes the condensing components by complexation. An illustrative macrocyclization is the synthesis of (−)-muscone from (+)-citronellal.
Stereocontrol 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,Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981-3996. while several others found crystallographic data J. D. Dunitz. Perspectives in Structural Chemistry (Edited by J. D. Dunitz and J. A. Ibers), Vol. 2, pp. l-70; Wiley, New York (1968) and NMR data Anet, F. A. L.; Degen, P. J.; Yavari. I. J. Org. Chem. 1978, 43, 3021-3023. 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.Casarini, D.; Lunazzi, L.; Mazzanti, A. Eur. J. Org. Chem. 2010, 2035-2056. 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.Evans, D. A.; Ripin, D.H.B.; Halstead, D.P.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 6816-6826.
Reaction classes used in synthesis of natural products under the macrocyclic stereocontrol model for obtaining a desired stereochemistry include: hydrogenations such as in neopeltolide Tu, W.; Floreancig, P. E. Angew. Chem. Int. Ed. 2009, 48, 4567-4571. and (±)-methynolide,Vedejs, E.; Buchanan, R.A.; Watanabe, Y. J. Am. Chem. Soc. 1989, 111, 8430-8438. epoxidations such as in (±)-periplanone B and lonomycin A,Evans, D.A.; Ratz, A.M.; Huff, B.E.; and Sheppard, G.S. J. Am. Chem. Soc. 1995, 117, 3448-3467. hydroborations such as in 9-dihydroerythronolide B,Mulzer, J.; Kirstein, H.M.; Buschmann, J.; Lehmann, C.; Luger, P. J. Am. Chem. Soc. 1991, 113, 910-923. enolate alkylations such as in (±)-3-deoxyrosaranolide, dihydroxylations such as in cladiell-11-ene-3,6,7-triol,Kim, H.; Lee, H.; Kim, J.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2006, 128, 15851-15855. and reductions such as in eucannabinolide.Still, W.C.; Murata, S.; Revial, G.; Yoshihara, K. J. Am. Chem. Soc. 1983, 105, 625-627.
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.Eliel, E.L., Wilen, S.H. and Mander, L.S. (1994) Stereochemistry of Organic Compounds, John Wiley and Sons, Inc., New York. Conformational analysis of odd-membered rings suggests they tend to reside in less symmetrical forms with smaller energy differences between stable conformations.Anet, F.A.L.; St. Jacques, M.; Henrichs, P.M.; Cheng, A.K.; Krane, J.; Wong, L. Tetrahedron 1974, 30, 1629-1637.
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.Petasis, N. A.; Patane, M.A. Tetrahedron 1992, 48, 5757-5821. 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.Pawar, D.M.; Moody, E.M.; Noe, E.A. J. Org. Chem. 1999, 64, 4586-4589. 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.Schreiber, S. L.; Smith, D. B.; Schulte, G. J. Org. Chem. 1989, 54, 5994-5996.
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.
Larger ring systems Similar principles guide the lowest energy conformations of larger ring systems. Along with the acyclic stereocontrol principles outlined below, subtle interactions between remote substituents in large rings, analogous to those observed for 8-10 membered rings, can influence the conformational preferences of a molecule. In conjunction with remote substituent effects, local acyclic interactions can also play an important role in determining the outcome of macrocyclic reactions.Deslongchamps, P. Pure Appl. Chem. 1992, 64, 1831-1847. The conformational flexibility of larger rings potentially allows for a combination of acyclic and macrocyclic stereocontrol to direct reactions.
Reactivity and conformational preferences The stereochemical result of a given reaction on a macrocycle capable of adopting several conformations can be modeled by a Curtin-Hammett scenario. In the diagram below, the two ground state conformations exist in an equilibrium, with some difference in their ground state energies. Conformation B is lower in energy than conformation A, and while possessing a similar 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 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 estimated from 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 value of ΔG0 between not just one, but many accessible conformations is the underlying energetic impetus for reactions occurring from the most stable ground state conformation and is the crux of the peripheral attack model outlined below.Seeman, J. I. Chem. Rev. 1983, 83, 83-134.
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.