Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain energy barrier to rotation is high enough to allow for the isolation of the conformers.[1][2] The word atropisomer is derived from the Greek a, meaning not, and tropos, meaning turn. The name was coined by Kuhn in 1933,[3] but atropisomerism was first detected in 6,6’-dinitro-2,2’-diphenic acid by Christie in 1922.[4] Oki defined atropisomers as conformers that interconvert with a half-life of at least 1000 seconds at a given temperature, which corresponds to an energy barrier or 93.3 kJ mol-1 at 300 K. [5] [6]
Atropisomers are an important class of compounds because they can display axial chirality or planar chirality. Atropisomers that display axial chirality contain different ortho substituents, which cause steric repulsion, ultimately leading to hindered rotation about the sp2-sp2 bond. The degree of steric repulsion correlates with the van der Waals radii of the particular substituent of interest. For example, a bromine substituent would lead to greater steric repulsion compared to a fluorine substituent. [1]
Atropisimers differ from other chiral compounds in that the equilibrated is predominantly thermally controlled whereas in the other forms of chirality, isomerization is usually only possible chemically. There are three basic factors that contribute to the stability of atropisomers: 1. steric bulk of substituents near the axis of rotation 2. length and rigidity of the bridge (e.g. the carbon-nitrogen bond length of N-phenylazoles is shorter than the carbon-carbon bond length of biphenyls) 3. chemical or photochemical induced rotation in addition to simply rotation due to thermal energy. [1] [6]
A variety of methods are employed to study atropisomers, including X-ray crystallography, electronic spectra, dipole moment measurements, basicity measurements, substituent constants (such as those from the Hammett plot), nuclear magnetic resonance, and optical methods. [6]
Stereochemical Assignment
editDetermining the axial stereochemistry of biaryl atropisomers can be accomplished through the use of a Newman projection along the axis of hindered rotation. The ortho, and in some cases meta substituents are first assigned priority based on Cahn–Ingold–Prelog priority rules. Starting with the substituent of highest priority in the closest ring and moving along the shortest path to the substituent of highest priority in the other ring, the absolute configuration is assigned P for clockwise and M for counterclockwise. In the example shown, A has priority over B. [1]
Synthesis
editOne way to synthesize these axially chiral biaryl compounds is through a direct atroposelective coupling e.g. Ullmann coupling, Suzuki-Miyaura reaction, or palladium-catalyzed arylation of arenes.[7] Two methods of achieving diastereoselective coupling are through the use of a chiral bridge that links the two aryl groups or through the use of a chiral auxiliary at one of the positions proximal to axial bridge. Enantioselective coupling can be achieved through the use of a chiral leaving group on one of the biaryls or under oxidative conditions that utilize chiral amines to set the axial configuration.[1]
Another method of synthesizing atropisomers is through the use of aromatic amides and thermodynamic control. By utilizing the planar rigid amide bond as seen in amino acids, and adding larger groups to the ortho position, chemists have been able to synthesize single atropisomers. Since atropisomers are thermally dependent, the thermodynamic control allows for selective synthesis under optimal conditions [8]
Scope
editIn one application the asymmetry in an atropisomer is transferred in a chemical reaction to a new stereocenter.[9] The atropisomer is an iodoaryl compound synthesised starting from (S)-valine and exists as the (M,S) isomer and the (P,S) isomer. The interconversion barrier between the two is 24.3 kcal/mol (101.7 kJ/mol). The (M,S) isomer can be obtained exclusively from this mixture by recrystallisation from hexanes. The iodine group is homolytically removed to form an aryl radical by a tributyltin hydride/triethylboron/oxygen mixture as in the Barton-McCombie reaction. Although the hindered rotation is now removed in the aryl radical, the intramolecular reaction with the alkene is so much faster than is rotation of the carbon-nitrogen bond that the stereochemistry is preserved. In this way the (M,S) isomer yields the (S,S) dihydroindolone.
Relaying Asymmetry of Transient Atropisomers
The most important class of atropisomers are biaryls such as diphenic acid, which is a derivative of biphenyl with a complete set of ortho substituents. Heteroaromatic analogues of the biphenyl compounds also exist, where hindered rotation occurs about a carbon-nitrogen or a nitrogen-nitrogen bond.[6] Others are dimers of naphthalene derivatives such as 1,1'-bi-2-naphthol. In a similar way, aliphatic ring systems like cyclohexanes linked through a single bond may display atropisomerism provided that bulky substituents are present. The use of axially chiral biaryl compounds such as BINAP, QUINAP and BINOL, have been found to be useful in the area of asymmetric catalysis as chiral ligands.
Their ability to provide stereoinduction has led to use in metal catalyzed hydrogenation, epoxidation, addition, and allylic alkylation reactions. [1] Other reactions that can be catalyzed by the use of chiral biaryl compounds are the Grignard reaction, Ullmann reaction, and the Suzuki reaction.[10] A recent example in the area of chiral biaryl asymmetric catalysis employs a five-membered imidazole as part of the atropisomer scaffold. This specific phosphorus, nitrogen-ligand has been shown to perform enantioselective A3-coupling. [11]
Biological Relevance and Natural Products
editMany atropisomers occur in nature. Some natural products can be used as drugs and an example of this is mastigophorene A. Mastigophorene A has been found to aid in nerve growth. [1][12]
Other examples of naturally occurring atropisomers include vancomycin isolated from an Actinobacterium, and knipholone, which is found in the roots of Kniphofia foliosa of the family Asphodelaceae. The structure complexity in vancomycin is significant because it can bind with peptides due to the complexity of its stereochemistry, which includes multiple stereocenters, two chiral planes in its stereogenic biaryl axis. Knipholone, with its axial chirality, occurs in nature and has been shown to offer good antimalarial and antitumor activities particularly in the M form.[1]
Knipholone
Drug Design
editThe pharmaceutical industry focuses its energy on producing enantiomerically pure compounds to be used as drugs. The use of atropisomers in synthesizing drugs allows for more stereochemical control. [13] One example is (-)-N-acetylallocolchinol, a drug that was discovered to aid in chemotherapy cancer treatment.[13][14]
Telenzepine is also an atropisomeric drug, and has a stereogenic C–N-axis in neutral aqueous solution it displays a half-life for racemization of the order of 1000 years. The enantiomers have been resolved. The activity is related to the (+)-isomer which is about 500-fold more active than the (–)-isomer at muscarinic receptors in rat cerebal cortex.[15]
However, drug design is not always aided by atropisomerism. In some cases, making drugs from atropisomers is challenging because isomers may interconvert faster than expected. Atropisomers also might interact differently in the body, and as with other types of stereoisomers, it is important to examine these properties before administering drugs to patients.[15]
References
edit- ^ a b c d e f g h Bringmann G, Mortimer AJP, Keller PA, Gresser MJ, Garner J, Breuning M (2005). "Atroposelective Synthesis of Axially Chiral Biaryl Compounds". Angewandte Chemie International Edition. 44 (34): 5384–5427. doi:10.1002/anie.200462661. PMID 16116589.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Anslyn and Dougherty, Modern Physical Organic Chemistry, University Science Books, 2006, ISBN 978-1-891389-31-3
- ^ Kuhn R (1933). "Molekulare asymmetrie". Stereochemie. Frendenberg, K. Ed.; Franz Deutike. p. 803.
- ^ Christie, George Hallatt (1 January 1922). "LXXI.?The molecular configurations of polynuclear aromatic compounds. Part I. The resolution of ?-6 : 6?-dinitro- and 4 : 6 : 4? : 6?-tetranitro-diphenic acids into optically active components". Journal of the Chemical Society, Transactions. 121: 614. doi:10.1039/CT9222100614.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Oki, M; Topics in Stereochemistry 1983, 1
- ^ a b c d Alkorta, Ibon; Elguero, José; Roussel, Christian; Vanthuyne, Nicolas; Piras, Patrick (2012). Atropisomerism and Axial Chirality in Heteroaromatic Compounds. Advances in Heterocyclic Chemistry. Vol. 105. pp. 1–188. doi:10.1016/B978-0-12-396530-1.00001-2. ISBN 9780123965301.
{{cite book}}: CS1 maint: date and year (link) - ^ Cepanec, Ivica (2004). Synthesis of biaryls (1st ed.). Amsterdam: Elsevier. ISBN 0080444121.
- ^ Clayden, Jonathan (2004). "Atropisomers and near-atropisomers: achieving stereoselectivity by exploiting the conformational preferences of aromatic amides". Chemical Communications (2): 127–135. doi:10.1039/b307976g. PMID 14737515.
- ^ Relaying Asymmetry of Transient Atropisomers of o-Iodoanilides by Radical Cyclizations Marc Petit, Andre J. B. Lapierre, and Dennis P. Curran J. Am. Chem. Soc.; 2005; 127(43) pp 14994 - 14995; (Communication) doi:10.1021/ja055666d Abstract
- ^ Cozzi, Pier Giorgio (2011). "Atroposelective Organocatalysis". Angew. Chem. Int. Ed. 50 (17): 3847–3849. doi:10.1002/anie.201008031. PMID 21448867.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Cardoso, Flavio S. P.; Abboud, Khalil A.; Aponick, Aaron (2 October 2013). "Design, Preparation, and Implementation of an Imidazole-Based Chiral Biaryl P,N-Ligand for Asymmetric Catalysis". Journal of the American Chemical Society. 135 (39): 14548–14551. doi:10.1021/ja407689a. PMID 24044433.
- ^ Fukuyama, Y. Asakawa (1991). "Novel neurotrophic isocuparane-type sesquiterpene dimers, mastigophorenes A, B, C and D, isolated from the liverwort Mastigophora diclados". J. Chem. Soc. Perkin Trans 1 (11): 2737–2741. doi:10.1039/p19910002737.
- ^ a b Zask, Arie (2013). "Biological Stereoselectivity of Atropisomeric Natural Products and Drugs". Chirality. 25 (5): 265–274. doi:10.1002/chir.22145. PMID 23620262.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Joncour, A (2006). "Biaryl axis as a stereochemical relay for the enantioselective synthesis of antimicrotubule agents". Anew. Chem. Int. Ed. 45 (25): 4149–4152. doi:10.1002/anie.200600451. PMID 16688690.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ a b J. Clayden, W. J. Moran, P. J. Edwards, S. R. LaPante: The Challenge of Atropisomerism in Drug Discovery, Angew. Chem. Int. Ed. 2009, 48, 6398-6401.