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Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the , , , and . Macrocycles describe a large, mature area of chemistry.
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. (2025). 9783527613809, Wiley-VCH. ISBN 9783527613809 The 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. The 15-membered ring is generated by ring-closing metathesis.
Early assumptions towards macrocycles in synthetic chemistry considered them far too floppy to provide any degree of stereochemical or regiochemistry 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.
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.
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.
Early investigations of macrocyclic stereocontrol studied 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."Classics in Stereoselective Synthesis". Carreira, Erick M.; Kvaerno, Lisbet. Weinheim: Wiley-VCH, 2009. pp 1-16.
Unlike the cyclooctanone case, alkylation of 2-cyclodecanone rings does not display significant diastereoselectivity.
However, 10-membered cyclic lactones display significant diastereoselectivity. 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. In contrast, when the methyl group was placed at the 7 position, a 1:1 mixture of diastereomers was obtained. 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.
Conjugate addition to the E-enone below 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.
Similar to intermolecular reactions, intramolecular reactions can show significant stereoselectivity from the ground state conformation of the molecule. In the intramolecular Diels-Alder reaction depicted below, the lowest energy conformation yields the observed product.Deslongchamps, P. J. Am. Chem. Soc. 2008, 130, 13989-13995. 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.Scheerer, J.R.; Lawrence, J.F.; Wang, G.C.; Evans, D.A. J. Am. Chem. Soc. 2007, 129, 8968-8969.
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.
Macrocycles often bind ions and facilitate ion transport across hydrophobic membranes and solvents. The macrocycle envelops the ion with a hydrophobic sheath, which facilitates phase transfer properties.
Macrocycles are often bioactive and could be useful for drug delivery.
Special focus is placed on macrocyclic peptides, as these are comparatively easy to produce. In addition, their risk is classified as comparatively low because, like the body's own proteins, they consist of Amino acid (which can, however, be modified). Normally it is difficult for molecules above a certain size and number of hydrogen bond donors and acceptors to get absorbed orally. However, it is now possible to make these molecules bio-orally available through certain modifications of the amino acids and through high N-alkylation. A chameleon-like behaviour of such molecules can also be observed, because the parts of the molecules that are directed outwards and inwards can change depending on the environment and thus influence the solubility.
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