Ultra-remote stereocontrol by conformational communication of information along a carbon chain

Many receptors and allosteric proteins function through binding of a molecule to induce a conformational change, which then influences a remote active site. In synthetic systems, comparable intramolecular information transfer can be effected by using the shape of one part of a molecule to control the stereoselectivity of reactions occurring some distance away. However, the need for direct communication with the reaction site usually limits such remote stereocontrol to distances of not more than about five bond lengths. Cyclic structures overcome this problem by allowing the controlling centre and the reaction site to approach each other, but the information transfer spans only short absolute distances. Truly remote stereocontrol can, however, be achieved with rigid compounds containing amide groups: the conformation of the amides can be controlled by stereogenic centres and responds to that of neighbouring amide groups and in turn influences stereoselective reactions. This strategy has allowed remote stereocontrol spanning 8 (ref. 11) or 9 (ref. 12) bonds. Here we demonstrate stereocontrol over a reaction taking place more than 20 bond lengths from the controlling centre, corresponding to a linear distance of over 2.5 nm. This transmission of information, achieved by conformational changes relayed through the molecule, provides a chemical model of allostery and might serve as a molecular mechanism for communicating and processing information.

[1]  J. Clayden,et al.  Lithium-sulfoxide-lithium exchange for the asymmetric synthesis of atropisomers under thermodynamic control. , 2002, Journal of the American Chemical Society.

[2]  S. Buchwald,et al.  A highly active Suzuki catalyst for the synthesis of sterically hindered biaryls: novel ligand coordination. , 2002, Journal of the American Chemical Society.

[3]  A. Mannschreck,et al.  Liquid Chromatography on Triacetycellulose, 14 Chromatographic Separation of Enantiomers and Barriers to Enantiomerization of Axially Chiral Aromatic Carboxamides , 1987 .

[4]  J. Pink,et al.  Barriers to rotation about the chiral axis of tertiary aromatic amides , 1998 .

[5]  G. Krauss.  Biochemistry of signal transduction and regulation , 1999 .

[6]  J. Clayden,et al.  Atroposelective attack of nucleophiles on 2-formyl-1-naphthamides and their derivatives: chelation and non-chelation control , 2000 .

[7]  J. Clayden,et al.  Conformational preference and remote (1,10) stereocontrol in biphenyl-2,2'-dicarboxamides. , 2001, Organic letters.

[8]  Victor Snieckus,et al.  Directed ortho metalation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics , 1990 .

[9]  J. Pink,et al.  Conformationally interlocked amides: Remote asymmetric induction by mechanical transfer of stereochemical information , 1998 .

[10]  Vincenzo Balzani,et al.  The bottom-up approach to molecular-level devices and machines. , 2002, Chemistry.

[11]  Clayden,et al.  Enantioselective Synthesis of Atropisomeric Amides by Dynamic Resolution: Thermodynamic Control with a Proline-Derived Diamine Resolving Agent. , 1999, Angewandte Chemie.

[12]  M. Helliwell,et al.  Using amide conformation to ‘project’ the stereochemistry of an (−)-ephedrine-derived oxazolidine: a pair of pseudoenantiomeric chiral amido-phosphine ligands , 2001 .

[13]  Max F. Perutz,et al.  Mechanisms of Cooperativity and Allosteric Regulation in Proteins , 1990 .

[14]  J. Clayden,et al.  Ephedrine as an auxiliary for the asymmetric synthesis of atropisomeric amides by dynamic resolution under thermodynamic control , 2001 .

[15]  C. Agami,et al.  Stereochemistry-60 : Kinetic control of asymmetric induction during oxazolidine formation from (-)-ephedrine and aromatic aldehydes , 1985 .

[16]  S. Miyano,et al.  Efficient 1,8- to 1,12-asymmetric induction in Grignard reactions of ω-keto esters by using BINOL or its 2′-oligoether derivatives as the chiral auxiliary , 1999 .

[17]  P. Linnane,et al.  Induction of molecular asymmetry by a remote chiral group , 1997, Nature.

[18]  P. Magnus,et al.  1,13 and 1,14 asymmetric induction: Remote control , 1997 .

[19]  T Mustelin.  Biochemistry of Signal Transduction and Regulation , 2002 .

[20]  M. Helliwell,et al.  Axial chirality in xanthene-4,5-dicarboxamides: 1,9-stereocontrol mediated by remote interactions between conformationally constrained amide groups , 2000 .

[21]  S. Miyano,et al.  Efficient 1,8- and 1,9-asymmetric inductions in the Grignard reaction of δ- and ε-keto esters of 1,1′-binaphthalen-2-ols with an oligoether tether as the 2′-substituent: application to the synthesis of (−)-malyngolide , 2001 .

[22]  M. Helliwell,et al.  Dynamic resolution of atropisomeric amides using proline-derived imidazolines and ephedrine-derived oxazolidines , 2004 .

[23]  M. Demuth,et al.  Short Biomimetic Synthesis of a Steroid by Photoinduced Electron Transfer and Remote Asymmetric Induction , 1999 .

[24]  Jean-Pierre Sauvage,et al.  Transition Metal-Containing Rotaxanes and Catenanes in Motion: Toward Molecular Machines and Motors , 1998 .

[25]  Ernest L. Eliel,et al.  Stereochemistry of Organic Compounds , 1962 .

[26]  M. Helliwell,et al.  ATROPOSELECTIVITY IN THE REACTIONS OF ORTHOLITHIATED AROMATIC TERTIARY AMIDES WITH ALDEHYDES , 1997 .