Academic literature on the topic 'Intramolecular contacts'

Biological macromolecules follow the same thermodynamic rules as inorganic or organic small molecules concerning supersaturation, nucleation, and crystal growth (1). Nevertheless macromolecules present particularities, because the intramolecular interactions responsible of their tertiary structure, the intermolecular interactions involved in the crystal contacts, and the interactions necessary to solubilize them in a solvent are similar. Therefore these different interactions may become competitive with each other. In addition, the biological properties of biological macromolecules may be conserved although the physico-chemical properties, such as the net charge, may change depending on the crystallization conditions (pH, ionic strength, etc.). A charged biological macromolecule requires counterions to maintain the electroneutrality of the solution; therefore it should be considered as a protein (or nucleic acid) salt with its own physico-chemical properties, depending on the nature of the counterions. To crystallize a biological macromolecule, its solution must have reached supersaturation which is the driving force for crystal growth. The understanding of the influence of the crystallization parameters on protein solubility of model proteins is necessary to guide the preparation of crystals of new proteins and their manipulation. Only the practical issues are developed in this chapter, and the reader should refer to recent reviews (2-4) for a description of the fundamental physical chemistry underlying crystallogenesis. The solubilization of a solute (e.g. a biological macromolecule) in an efficient solvent requires solvent-solute interactions, which must be similar to the solvent-solvent interactions and to the solute-solute interactions of the compound to be dissolved. All of the compounds of a protein solution (protein, water, buffer, crystallizing agents, and others) interact with each other via various, often weak, types of interactions: monopole-monopole, monopole-dipole, dipole-dipole, Van der Waals hydrophobic interactions, and hydrogen bonds. Solubility is defined as the amount of solute dissolved in a solution in equilibrium with its crystal form at a given temperature. For example, crystalline ammonium sulfate dissolves at 25°C until its concentration reaches 4.1 moles per litre of water, the excess remaining non-dissolved. More salt can be dissolved when raising the temperature, but if the temperature is brought back to 25°C, the solution becomes supersaturated, and the excess of salt crystallizes until its concentration reaches again its solubility value at 25°C (4.1 moles per litre of water).

En route to sarcandralactone A 3, Scott A. Snyder of Scripps Florida effected (Angew. Chem. Int. Ed. 2015, 54, 7842) Diels–Alder cycloaddition of the activated enone 1 to the Danishefsky diene. On exposure to trifluoroacetic acid, the adduct was unraveled to the ene dione 2. Michael N. Paddon-Row of the University of New South Wales and Michael S. Sherburn of the Australian National University prepared (Nature Chem. 2015, 7, 82) the allene 4 in enantiomerically-pure form. Sequential cycloaddition with 5 followed by 6 gave an adduct that was decarbonylated to 7. Further cycloaddition with nitro­ethylene 8 led to the pseudopterosin (−)-G-J aglycone 9. The protein–protein interaction inhibitor JBIR-22 12 contains a quaternary α-amino acid pendant to a bicyclic core. Nicholas J. Westwood of the University of St. Andrews set (Angew. Chem. Int. Ed. 2015, 54, 4046) the absolute configuration of the core 11 by using an organocatalyst to activate the cyclization of 10. Metal catalysts can also be used to set the absolute configuration of a Diels–Alder cycloaddition. In the course of establishing the structure of the marine natural prod­uct muironolide A 15, Armen Zakarian of the University of California, Santa Barbara cyclized (J. Am. Chem. Soc. 2015, 137, 5907) the enol form of 13 preferentially to the diastereomer 14. Unactivated intramolecular Diels–Alder cycloadditions have been carried out with more and more challenging substrates. A key step in the synthesis (Chem. Asian. J. 2015, 10, 427) of (−)-platencin 18 by Martin G. Banwell, also of the Australian National University, was the cyclization of 16 to 17. In another illustration of the power of the unactivated intramolecular Diels–Alder reaction, Thomas J. Maimone of the University of California, Berkeley cyclized (Angew. Chem. Int. Ed. 2015, 54, 1223) the tetraene 19 to the tricycle 20. Allylic chlo­rination followed by reductive cyclization converted 20 to chatancin 21.

The fungal secondary metabolite (+)-pleuromutilin 3 exerts antibiotic activity by binding to the prokaryotic ribosome. Semisynthetic derivatives of 3 are used clinically. The central step of the first synthesis of (+)-pleuromutilin 3, devised (Chem. Eur. J. 2013, 19, 6718) by David J. Procter of the University of Manchester, was the SmI2-mediated reductive closure of 1 to the tricyclic 2. The starting material for the synthesis was the inexpensive dihydrocarvone 4. Ozonolysis and oxidative fragmentation following the White protocol delivered 5 in high ee. Conjugate addition with 6 followed by Pd-mediated oxidation of the resulting silyl enol ether gave the enone 7. Subsequent conjugate addition of 8 proceeded with modest but useful diastereoselectivity to give an enolate that was trapped as the triflate 9. The Sakurai addition of the derived ester 10 with 11 led to 12 and so 1 as an inconsequential 1:1 mixture of diastereomers. The SmI2-mediated cyclization of 1 proceeded with remarkable diastereocontrol to give 2. SmI2 is a one-electron reductant that is also a Lewis acid. It seems likely that one SmI2 bound to the ester and the second to the aldehyde. Electron transfer then led to the formation of the cis-fused five-membered ring, with the newly formed alkoxy constrained to be exo to maintain contact with the complexing Sm. Intramolecular aldol condensation of the resulting Sm enolate with the other aldehyde then formed the six-membered ring, with the alkoxy group again constrained by association with the Sm. Hydrogenation of 13 gave 14, which could be brought to diastereomeric purity by chromatography. Elegantly, protection of the ketone simultaneously selectively deprotected one of the two silyl ethers, thus differentiating the two secondary alcohols. Reduction of the ester to the primary alcohol then delivered the diol 15. Selective esterification of the secondary alcohol followed by thioimidazolide formation and free radical reduction completed the preparation of 16. Ketone deprotection followed by silyl ether formation and Rubottom oxidation led to the diol 17. Protection followed by the addition of 18 and subsequent hydrolysis and reduction gave the allylic alcohol 19.