WO2011050153A1 - Mouvement d'un objet chiral - Google Patents

Mouvement d'un objet chiral Download PDF

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Publication number
WO2011050153A1
WO2011050153A1 PCT/US2010/053525 US2010053525W WO2011050153A1 WO 2011050153 A1 WO2011050153 A1 WO 2011050153A1 US 2010053525 W US2010053525 W US 2010053525W WO 2011050153 A1 WO2011050153 A1 WO 2011050153A1
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WIPO (PCT)
Prior art keywords
chiral
chiral objects
application
objects
motion
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Application number
PCT/US2010/053525
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English (en)
Inventor
Mirianas Chachisvilis
Osman Kibar
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Dynamic Connections, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Dynamic Connections, Llc filed Critical Dynamic Connections, Llc
Publication of WO2011050153A1 publication Critical patent/WO2011050153A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
    • B01J19/087—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing electric or magnetic energy

Definitions

  • This description relates to motion of a chiral object.
  • chiral object or chiral system
  • chiral object very broadly to include, for example, any "original” object or system that differs from a mirror image of the original object such that a mirror image of the original cannot be superimposed on the original.
  • chiral object is a chiral molecule, also called an enantiomer.
  • a common feature of a chiral molecule is its "handedness" (i.e., right-handed or left-handed).
  • Enantiomers are a subset of chiral objects called stereoisomers. As shown in figure 1, a stereoisomer is one of a set of isomeric molecules 2, 4.
  • a stereoisomer includes at least one stereocenter, which is any atom that bears groups such that an interchanging of any two groups leads to a different stereoisomer of the set.
  • a stereoisomer may have more than one stereocenter.
  • Chirality is important in chemistry, especially for biological and drug applications.
  • Natural bio-molecules are typically found in only one enantiomeric form (e.g., proteins, peptides, and amino acids in the human body are all left-handed, and sugars are all right-handed).
  • the fields of drug discovery, development, and manufacturing are interested in samples of molecules that are enantiopure (i.e., contain only one enantiomeric form, all left-handed or all right-handed; we sometimes use the word "form" to refer to a "handedness”), because one form of enantiomer may work better in vivo while the opposite form may be toxic or may cause side effects.
  • chemistry-based fields would also benefit from enantiopure samples of molecules, including (for illustration purposes), but not limited to: flavors and fragrances, agrichemicals, fine chemicals, and others.
  • Some molecular separation techniques are not effective for chiral molecules, because two counterpart enantiomers generally share physical properties, including chemical composition, charge, size, electric and magnetic dipole moments 8, and energy levels. Detection and separation of counterpart chiral molecules is typically done by interacting the molecules with a chiral medium (e.g., a chemical matrix). Enantiomers also can be identified by their interaction with a chiral (e.g., circularly polarized) electromagnetic field.
  • a chiral medium e.g., a chemical matrix
  • Enantiomers also can be identified by their interaction with a chiral (e.g., circularly polarized) electromagnetic field.
  • directional motion of chiral objects in a mixture is caused by rotation of the chiral objects produced by a field that is applied across, and rotates relative to, a chamber; and a computer-implemented step determines or uses, or determines and uses, in an application or process, a feature of a coupling between the rotational and the translational motion of the chiral objects.
  • Implementations may include one or more of the following features.
  • the feature of the coupling comprises a direction of the directional motion of the chiral objects for a given direction of the rotation of the field.
  • the feature comprises a magnitude of the directional motion of the chiral objects for given parameters of the field, or of an apparatus that causes the directional motion, or of both.
  • the feature comprises a distribution of directions or magnitudes or both of the directional motion of the chiral objects, over a set of configurations or structures of the chiral objects.
  • the application or process comprises an analysis application or process.
  • the analysis application or process comprises a determination of an absolute configuration or stereochemistry of the chiral objects.
  • the analysis application or process comprises a determination of a presence or absence of the chiral objects.
  • the analysis application or process comprises a purity analysis of the chiral objects.
  • the application or process comprises a preparative application or process.
  • the preparative application or process comprises an isolation of the chiral objects.
  • the preparative application or process comprises an enrichment of the chiral objects.
  • the preparative application or process comprises a separation of the chiral objects.
  • the feature is provided for use in controlling, as feedback to, or as a result for use in, an apparatus, or for use in a combination of them.
  • the feature is provided to a user as at least one of information, a result, or feedback.
  • the user comprises a human or a machine or both.
  • a device for use in connection with directional motion of chiral objects in a mixture— the directional motion being caused by rotation of the chiral objects produced by a field that is applied across, and rotates relative to, the chamber— a device is configured to determine or use, or to determine and use, in a step of an application or process, a feature of the coupling between the rotational and the translational motion of the chiral objects.
  • the device comprises software (including computer implemented steps, for example) running on a computer, hardware, or a combination of them.
  • Figure 1 is an illustration of molecules.
  • Figure 2 is an illustration of molecular structures.
  • Figure 3 is an illustration of hydrodynamic chirality and directional motion.
  • Figure 4 is a distribution profile of hydrodynamic chirality.
  • Figure 5 is a flow diagram.
  • Figure 6 is a flow diagram.
  • Figure 7 is a block diagram.
  • HERO Chiral Separation by Propeller Motion
  • separation and manipulation of chiral objects can be achieved without using chiral media, instead by relying on the susceptibility of the objects to external influences (e.g., forces) and the handedness of the objects.
  • the dipole moment that characterizes chiral molecules is susceptible to being rotated by a rotating external electric field.
  • the left handedness or right handedness of counterpart enantiomers for example, can be used to transform the rotational motion of the enantiomers into translational (i.e., directional) motion of each of the
  • the handedness of some molecules is similar to the opposite handedness of left-handed and right-handed macroscopic propellers, which (when rotated) can propel themselves and objects to which they are attached in respectively opposite directions through a medium.
  • the "propeller" of each molecule is characterized by a spatial configuration associated with its chiral features. As the propeller rotates, these spatial features act against fluid resistance of the mixture that holds the molecules, to force the propeller and the molecule to move in a direction. We sometimes refer to this transformation of rotational motion of the propeller into directional motion depending on the handedness of the propeller as the propeller effect.
  • an external rotating electrical field is applied to a sample of chiral molecules.
  • each chiral molecule (which is an example of a feature of a molecule that is susceptible to an external influence) lines up with the external electric field and rotates with it causing rotation of the chiral molecules (this rotation being an example of motion of the molecule in response to the external influence).
  • the handedness (i.e., chirality or chiral features) of the molecule (which can be viewed as a tiny propeller) transforms this rotation into a linear (i.e., directional or translational) motion (E. M. Purcell, "The efficiency of propulsion by a rotating flagellum," Proc. Natl. Acad. Sci. USA, Biophysics, v94, pp 11307-11311, Oct. 1997).
  • the magnitude and profile of the concentration gradient for each enantiomer, and thus, the enrichment achieved, will depend on the enantiomer 's propeller efficiency (that is, the efficiency with which its spatial configuration converts the rotation induced by the external influence to a translational force on the molecule, which relates to the size, shape and orientation of the propeller, among other things), the effective length of the container that holds the mixture, how long the field is applied, the electric field strength, the frequency of rotation, and properties of the fluid in which the enantiomers are held in the mixture, among other things.
  • propeller efficiency we sometimes refer to the propeller efficiency as the propeller propulsion efficiency.
  • a molecule to a form molecular chirality is typically based on a predetermined set of rules that are arbitrary.
  • designated chirality of a molecule is not directly associated with any directly measurable physical property of the molecule (except its structure), because the chirality only defines a particular configuration of molecular structure.
  • the propeller effect causes motion of the molecule in a propulsion direction 16.
  • the magnitude of the hydrodynamic chirality parameter specifies the propeller efficiency defined as a translational displacement 17 of the chiral molecule in the propulsion direction that is caused by one complete (360 degrees) rotation/revolution 18 of the molecule under the influence of the external field 14.
  • the direction of translational motion is expressed as a sign (e.g., plus or minus) of the propeller efficiency value for a specific direction of rotation.
  • a sign e.g., plus or minus
  • a standard direction of rotation of the external field to correspond to a motion of a right-hand screw.
  • Positive and negative hydrodynamic chirality correspond to directions of motion along or against the direction of motion of a right-hand screw, respectively.
  • hydrodynamic chirality characterizes the coupling between rotational and translational degrees of freedom in chiral molecules, i.e., hydrodynamic chirality characterizes the ability and efficiency of chiral molecules to propel under the influence of an external rotating field and is quantified through sign and magnitude of propeller efficiency.
  • Hydrodynamic chirality can be characterized either with respect to a configuration of molecules of a particular 3-D structure for the enantiomer group to which the molecules belong, or (as shown in figure 4) with respect to a distribution profile 22, 24 of propeller efficiencies 26 for two or more of the different
  • hydrodynamic chirality i.e., chiral molecules of S or R absolute configurations propel to opposite directions under the influence of a given external rotating field.
  • its absolute configuration (as between S and R) can be determined by comparing the determined direction of motion with the predicted sign of hydrodynamic chirality of that particular enantiomer.
  • Hydrodynamic chirality can be determined and then used in a wide variety of ways and for a broad range of practical applications.
  • performance of a system can be predicted 54, and/or the absolute configuration of the molecule can be determined 56.
  • the predicted performance, the determined absolute configuration, and/or other results can be used to control a process or instrument or to provide feedback to a user or both 58.
  • results can be presented to a user 60. /. Structure and dipole moment determination
  • energy and electrical dipole moment of the molecule can be determined using a number of existing standard molecular modeling techniques which include ab initio, density functional or molecular mechanics methods. Lowest energy structure and structures of all other thermally accessible conformations can be optimized and their energies (heat of formation) and dipole moments calculated.
  • An enantiomer chiral molecule (solute) is put into a box filled with solvent molecules (in a simulation context) and a molecular dynamics (MD) simulation is performed in the presence of a simulated rotating electric field.
  • MD molecular dynamics
  • Molecular dynamics takes into account all possible interactions between atoms in the combined solute-solvent system.
  • MD enables assessment of the importance of specific interactions with the solvent and also estimates the effects of rotation of solvent molecules on the solute.
  • the axial position of the center of mass of the molecule is recorded.
  • the total axial displacement in the simulation is divided by the total number of revolutions of the molecule in the simulation to obtain the magnitude of the propeller efficiency, i.e., displacement per one revolution. The sign is obtained from the direction of displacement determined in the simulation.
  • This method provides an approximate estimate of the sign of propeller effect based on integration of angular momentum of the solute due to multiple interactions with randomly impinging solvent molecules. This approach could be suitable for quick qualitative determination of absolute configuration.
  • a solute molecule can be modeled as a collection of spheres where interactions between spheres are included via the Oseen-Burgers hydrodynamic interaction tensor.
  • molecules with complicated shapes can be modeled by covering their isodensity surface with infinitely small spheres. This method has been used
  • propulsion velocity separation time, purity level, throughput, and others such as power, heating, convection, solvent, chiral labels).
  • propulsion velocity separation time, purity level, throughput, and others
  • hydrodynamic chirality can also be used in a particular application, e.g. comparing direction of the translational motion of chiral objects in an apparatus with the predicted direction from simulations to determine absolute stereochemistry.
  • the particular application or process that makes use of the hydrodynamic chirality may be an analysis application or process (e.g. determination of absolute configuration or stereochemistry, determination of absence or presence, or purity analysis of the chiral objects); or it may be a preparative application or process (e.g. isolation, enrichment, or separation of the chiral objects) 82.
  • Every possible application can be considered one or the other of analysis and preparation, and the only distinction between the two of those is that in analysis, the chiral molecules or objects are not used at the end of an analysis application, but they are collected and used in a subsequent step in a preparation application.
  • An interaction with an apparatus may comprise controlling the apparatus, providing feedback to it, using a result towards the operation or functionality of the apparatus, or a combination of them.
  • the interaction may be with a user (e.g. a human, or a computer), to provide the user with information about the apparatus and/or the processes run with that apparatus, with a result or outcome, with feedback, or with a combination of them.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Selon l'invention, le mouvement directionnel d'objets chiraux dans un mélange est provoqué par la rotation d'objets chiraux produite par un champ qui est appliqué dans une chambre et tourne par rapport à celle-ci; une étape mise en œuvre par ordinateur consiste à déterminer et/ou utiliser, dans une application ou un procédé, une caractéristique d'un couplage entre les mouvements de rotation et de translation des objets chiraux.
PCT/US2010/053525 2009-10-23 2010-10-21 Mouvement d'un objet chiral WO2011050153A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US25438809P 2009-10-23 2009-10-23
US61/254,388 2009-10-23

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WO2011050153A1 true WO2011050153A1 (fr) 2011-04-28

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5398037A (en) * 1988-10-07 1995-03-14 The Trustees Of The University Of Pennsylvania Radomes using chiral materials
US20080262240A1 (en) * 2007-04-17 2008-10-23 Osman Kibar Separation And Manipulation Of A Chiral Object
US20080274555A1 (en) * 2007-04-17 2008-11-06 Dynamic Connections, Llc Separation and Manipulation of a Chiral Object
US20090239281A1 (en) * 2008-03-21 2009-09-24 Dynamic Connections, Llc Moving A Small Object in A Direction

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5398037A (en) * 1988-10-07 1995-03-14 The Trustees Of The University Of Pennsylvania Radomes using chiral materials
US20080262240A1 (en) * 2007-04-17 2008-10-23 Osman Kibar Separation And Manipulation Of A Chiral Object
US20080274555A1 (en) * 2007-04-17 2008-11-06 Dynamic Connections, Llc Separation and Manipulation of a Chiral Object
US20090239281A1 (en) * 2008-03-21 2009-09-24 Dynamic Connections, Llc Moving A Small Object in A Direction

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