Remote functional groups enhance binding through preorganization.

Remote functional groups enhance binding through preorganization.

Te&&dmnL&ters. Rited oo4o-4039/90 53.00 + .oo Pcrgamon Press plc Vo131. No.36, pi 512145124.1~ in Great Britain Remote Functional Groups Enhance B...

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Te&&dmnL&ters. Rited

oo4o-4039/90 53.00 + .oo Pcrgamon Press plc

Vo131. No.36, pi 512145124.1~

in Great Britain

Remote Functional Groups Enhance Binding Through Preorganization. N. Horiuchi, J. Huff and J. Rebek, Jr.’ Department of Chemistry, Massachusetts Institute of Technology Cambridge, MA 02139


Rotational restrictions in synthetic receptors lead to increased binding affinity by

reducing the number of unfavorable conformations. How things fit together is the domain of molecular recognition; how well things fit together depends on their predisposition to do so. This matter, frequently referred to as “preorganization,“* involves separating enthalpic effects - destabilization of the ground states - from entropic effects involving restricted rotations.

The distinction is difficult to make with small structures such as o-

phenanthroline or l&crown-6, since organizing the site for binding usually destabilizes the ground state.2 We have developed a method to examine the issue by using large cleft-like structures with remote steric effects to restrict conformations3 and report here our results. The structures make use of triaryl benzenes as scaffolds or spacers; they hold apart three carboxyl groups provided by Kemp triacid4 subunits. In structure 1, rotation about the CaVl-N bond permits divergent acid conformations and rotation about the Caryl-Car,,1 bonds permit cis/trans isomers to interconvert.

In structure 2, the ortho methyl groups enforce convergence of the OH

bonds of the carboxyl functions but cis and trans isomers remain; in structure 3, two sites are present, and preorganization for binding is maximal. The molecules were prepared (Eq. 1) by acid catalyzed trimerizations of the appropriate nitroacetophenone followed by reduction of 4 (Hz/Ra-Ni)6 to the amines, 5. Condensation with the anhydride acid chloride4 of Kemp’s triacid 6 gave the appropriate receptors. The final condensations usually gave >25% yields except in the case of the hexaacid 3 (17%). Titrations were performed by NMR in CD3CN using hexamethylene tetramine 7 or derivatives of the triamine 8 as the guest species. estimates are flO%.

The saturation plots were used to generate non-linear least squares fits; error Changes in chemical shifts of the aryl portion of the receptors were generally

used. 5121




5aX=NY,R=Y=H 4bX=N02,RrCH3,Y=H 5bX=NH2,RrCH1,YrH

0 O$J-Ad

4cX=Y=N&,R=CH3 ‘W3


lR=H 2 R -_ CU.



For the complexes, exchange between free and bound amines was rapid at room temperature, but could be frozen out at low temperatures. For example, receptor 1 with excess 7 at 220’K in CD2C12 gave separate signals for free and bound 7. Further lowering of the temperature to 195°K resolved the hydrogen signals indicated for the complex 9. The titration data is given in the Table. Table Association constants (M-1) for azadamantanes and the synthetic receptors, 24’C; CD3CN Receptor

Amine 7











SbfR=Bd 170

Sc(R=N02) 50



K1 = 95Ob

K1 = 23Ob

K2=%0 K2=250 a no regular changes in chemical shift were observed in either host or guest spectra during the titration. b The asswiation

constants are statistically corrected.

Sax-Ii SbX.Br


Three trends can be seen from the data. First, basicity of the amines plays a role; the more basic amines show higher affinity to a given receptor. Second, the preorganization factor is apparent. The 1.5 to 3.5fold enhancement of binding induced by the remote methyl groups of 2 is somewhat smaller than the 4-fold expected on purely entropic grounds (the methyls reduce the number of ground state conformations available to 2 vs. 1 by this factor). Third, no cooperativity of


the allosteric sort is apparent. The binding of the triamines at the first site of the hexaacid 3 is also enhanced by nearly two-fold over 2 as would be expected on statistical grounds. Thus the free state of 3 probably resembles the conformation of its complexes with the amines. In summary, large spacers can sufficiently separate functional groups to isolate the entropic effects from the enthalpic effects involved in preorganization.

Allosteric effects can be regarded as

one means by which nature has evolved to overcome the enthalpic price of preorganizing active sites; binding forces at remote sites force the active sites into their on or off positions.


We thank the National Institutes of Health for support of this research.

References 1) Cram, D.J.; Science 1988,240,760-767. 2) Rebek, J. Jr. Science 1987,235, 1478; Still, W.C. Heterocyclic Chem.1987,24 (Suppl. 9) S33-S42. 3) The use of such effects to preorganize polyethers has recently been described: Iimori, T.; Still, W.C. I. Am. Chem. Sot. 1989, III,34394440;Iimori, T.; Erickson, S.D.; Rheingold, A.L.; Still, W.C. Tefrahedron Left. 1989,30, 69476950. 4) Kemp, D.S.; Petrakis, K.S. 1. Org. Gem. 1981,46, 5140. The triacid is commercially available from the Aldrich Chemical Co. 5) Ebmeyer, F.; Vogtle, F. Angew. Chem. 1989,101,95. 6) All new compounds were characterized by a full complement of high resolution spectra; FAB spectra were obtained on 1,2, and 3.. For 1 mp 32O”Q). 2 and 3 showed mp > 35O’C. (Received in USA 19 June 1990)