2828
Journal of the American Chemical Society
/ 100:9 / April 26, 1978
Host-Guest Complexation. 10. Designed Chiral Recognition in Solution between Carboxyl-Containing Macrocyclic Polyethers and an a-Amino Acid l y 2 Joseph M. Timko, Roger C. Helgeson, and Donald J. Cram* Contribution No. 3888 from the Department of Chemistry, University of California, Los Angeles, California 90024. Received September 6, I977
Abstract: Twelve racemic macrocyclic polyethers have been examined for their amenability to optical resolution through differential complexation with L-valine. The hosts were designed to test a model (structure 13) for chiral recognition in complexation in solution based on complementary placement of binding sites and steric barriers in L-valine and hosts of the S configuration. The hosts contained one 1,l'-dinaphthyl chiral unit 'oined through oxygens in its 2,2' positions to a polyethylene glycol in which D is the dinaphthyl and E the CHzCH2 unit. In the chain to form macrocycles of the general structure, &, model envisioned for the complex (13), the macrocycle of the host is the central hydrogen bonding site for the NH3+ group of valine. Two additional binding sites are provided by two identical side chains, - C H ~ O C H ~ C O Zattached H, at the 3,3' positions of the 1,l'-dinaphthyl unit. The terminal carboxyl groups are separated by one being located on one side and the other being located on the opposite side of the macroring. One carboxyl group of the host was designed to hydrogen bond with the carboxyl of the valine guest, and the second in its anionic form to contact ion pair with the NH3+ group of the valine. In the envisioned (1) and valine (one of which is 13), the two chiral elediastereomeric complexes between 3,3'-(H02CCH20CH2)2DmO)5 ments are adjacent. In the complexes of the L-Sor D-R configurations, the chiral elements are sterically complementary, but in those of the L-R or D-Sconfigurations they are noncomplementary. This model was tested by distributing racemic 1 and Lvaline between two layers composed of CD3C02D-CDCI3-D20 in proportions that placed essentially all the valine and half the host in the D2O-rich layer, and the other half of the host in the CDC13-rich layer. The L-valine complexed the S enantiomer of 1, 2.9 times better than the R enantiomer of 1 in the D2O-rich phase. Through liquid-liquid chromatography, racemic 1 in the mobile phase was resolved by L-valine in the stationary phase into its optically pure enantiomers. By distributing racemic valine and (S)-1 between two layers composed of CD3CO2D-CDCI3-D2O of different proportions than before, essentially all the host remained in the CDC13-rich layer complexed with an equivalent of valine, and the remaining valine was in the D20rich phase. The factor by which (S)-1 preferred to complex L. over D-Vahe in the CDC13-rich phase was 1.5. To determine which structural components of 1 were necessary to its chiral recognition properties, 11 variants of 1 were tested. The requirements for highly structured molecular complexation in solution are discussed.
Biological chemistry includes a description of the state to which naturally occurring organic compounds have evolved. The survival capacity of these organic systems is critically dependent on structural recognition in complexation between organic entities in solution. Much of the direction of molecular traffic in, out of, and within the cell depends on complementary vs. noncomplementary structural relationshipsbetween organic entities. Since most biological compounds are asymmetric, chiral recognition is one of the cornerstones of structural recognition in complexation, and, therefore, one of the fundamental features of molecular evolution. Studies of structural molecular complexes between organic compounds in solution not involving enzymes or genes have centered on the naturally occurring cyclodextrins as host corn pound^^^-^ and on catalysis or inhibition of reaction rates through c o m p l e ~ a t i o n . ~Most ~ - ~ optical resolutions of racemates involve differences in formation rates or in energies of crystal lattices of d i a ~ t e r e o m e r s . ~ ~ Others - ~ , ~ J ~involve ~ solid-liquid3n-rqv or gas-liquid c h r o r n a t ~ g r a p h y ~or ~ -di~>~ a l y ~ i sDistributions .~~ of the enantiomers of a racemate between water and optically active liquid^^^,^ gave a maximum optical purity of 2 f 0.9%.3uA complete optical resolution by countercurrent extraction has a ~ p e a r e d . ~ y This series of papers describes the design and synthesis of organic host compounds that contain convergent binding sites arranged to contact divergent binding sites of selected guest compound^.^ Binding sites thus far incorporated into hosts include ether oxygen^,^ t h i o e t h e r ~ ,carboxyl^,^^^^^^ ~~ ester~,~e,hJ amides,4i tertiary furan and tetrahydrofuran ~ x y g e n s , ~pyridyl ~ - g nitrogens,&,garomatic T bases,4e phenolic hydroxyls,5a methoxyl oxygen^,^^ and P-diketone group^.^^,^ Hydrocarbon units that extend rigidly in three dimensions have been incorporated into host compounds to provide them with shape in the form of steric or chiral barriers. 0002-7863/78/1500-2828$01 .OO/O
The d i ~ h e n y l , ~dgi n a ~ h t h y l , ~ gd, ~i t, e' t r a l ~ l and , ~ ~ [2.2]paracyclophanyl units4f have thus far been employed. Different individual binding forces holding host to guest that have been identified thus far include ArN2+. * .0(CH2)2,4a (NH2)2C=NH+. .0(CH2)2,4a RNH3+- . N ( p ~ r i d y l ) , ~ ~ RNH3+--.0(CH2)2,4a RNH3+-. -D2C,4dRN+...0(CH2)2,4a RN+- .02CR,2b RN+. .0=C(OCH3)R,4d RN+. - T - A ~ , ~ ~ ROH. .0(CH2)2,4i Ar0H.a .O(CH2)2,5d RNH3+. O ( C H ~ ) A T M+. , ~ ~ .0(CH2)2,5a-CM+.- .02C,4d3iM+. T - A ~M+. , ~ ~. O ( C H ~ ) A I -and , ~ ~M+. .OC=C-.Sb,c Several criteria have been used for complex formation and for the structures of the complexes between organic hosts and guests. These include crystallizatior~~c~~~~~~~ and determination of the crystal structure of complexes,6 'H NMR chemical shift comparisons between components and c o m p l e x e ~ , ~ ~ , e , ~ , ~ ~ , ~ lipophilizationby complexing of polar guests by nonpolar hosts in nonpolar media,2*4a-f,i,5d,e and determination of association constants as a function of systematic structure changes in hosts and g u e s t ~ . ~ ~ - ~ J ~ One of the most appealing criteria for the structures of complexes in solution makes use of thermodynamic chiral recognition. Two enantiomers of a guest racemate are put in competition with one another for complexing one enantiomer of a host or, conversely, two enantiomers of a host racemate are put in competition with one another for complexing one enantiomer of a guest. The extent to which one diastereomer dominates over the other at equilibrium measures the degree of chiral recognition. The direction of the stereochemical bias in chiral recognition is given by the relative configurations of the host and guest in the more stable diastereomeric comp l e ~ . ~ ~ ,Comparisons ~ ~ , g v ~ between observation and expectation of the directions of the bias and the degrees of chiral recognition as a function of systematicallychanged structures of hosts and guests provides a practical means of identifying structural
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0 1978 American Chemical Society
- -6
Timko, Helgeson, Cram
/
2829
Host-Guest Complexation
parameters responsible for stereochemical selection in comple~ation.~g In our initial studies, the a-amino acids or their derivatives have been selected as guests for several reasons. (1) They are important enzyme substrates. (2) They possess highly polar binding sites that diverge from their chiral centers. (3) They provide a chiral series of structurally related available compounds whose absolute configurations, maximum rotations, and optical stabilities are known. The host design was primarily based on the convergent placement of binding sites and chiral steric barriers in positions to complement their divergent counterparts in the a-amino acid guests. Possible host-guest structural relationships were visualized through examination of Corey-Pauling-Koltun (CPK) molecular models of potential complexes of the aamino acids. Criteria applied to specific host selection were as follows. (1) The hosts had to contain binding sites for the NH3+ and COzH (or COz-) groups of the a-amino acids. (2) Their chiral steric barriers had to be located in the envisioned complex close to the asymmetric center of the a-amino acid, and one complex in the molecular models had to appear more stable sterically than its diastereomeric alternative. (3) The hosts had to be amenable to systematic structural changes to establish the roles played in chiral recognition by the various molecular parts. (4) The hosts had to undergo a minimum amount of reorganization during complexation. ( 5 ) The parent hosts had to have Cz axes so that the same complex was formed when the guest was complexed on either face of the macroring. (6) The host structures had to be as simple as possible. (7) The hosts had to possess a balance between hydrophilic and lipophilic properties that allowed them to be distributed between polar and nonpolar liquid phases. (8) The hosts had to be synthesizable on a scale large enough to produce workable quantities of compounds. This paper describes the chiral recognition game played mainly in the “guest distinguishes between hosts” direction. Valine was selected as a standard guest because its isopropyl group has a moderately large steric requirement, because it possesses the desired hydrophilic-lipophilic balance, and because both enantiomers can be purchased. The first section of the paper describes the model for the complexes on which the host selection was based. The second section deals with the test system used to measure the degree and direction of configurational bias in chiral recognition. The third section illustrates an application of chiral recognition in complexation to the total resolution of a racemic host. In the fourth section, the structural parts of the parent host required for chiral recognition are identified. The fifth section describes the results of a survey of other potential hosts. Results and Discussion Model for Complexes on Which Host Selection Was Based. The hosts selected and synthesized for this study possess structures 1-12. Their syntheses, maximum rotations, absolution configurations, and optical stabilities have been reported4g.i (compounds 3-5 were only prepared as racemates). These potential hosts all contain the chiral, optically stable 1,l’-dinaphthyl element attached at its 2,2’ positions through oxygens to a polyethylene glycol chain to form a macrocyclic ring. The cyclic ether oxygens are evenly spaced throughout the ring, which in their more stable gauche conformations’ provide a hole on whose center the oxygen’s electron pairs roughly converge. In CPK models, the two naphthalenes occupy planes roughly perpendicular to the best plane of the macroring, one protruding from one face tangent to the macroring, and the other from the other face tangent to the macroring. Substituents attached to the 3,3’ positions of the naphthalenes extend into the space on the two faces of the
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macroring, and are separated from one another by the macroring. In CPK molecular models, parent host 1 of the S configuration appeared capable of complexing L-valine in a complementary way to give complex 13. This structure is formed by 0
II
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a proton transfer from the diacid host to the zwitterionic guest, and by hydrogen bonding and ion pairing of the resulting salt. In 13, the six-oxygen macroring neatly hydrogen bonds the NH3+ group in a tripod arrangement, which places the axis of the C*-N bond parallel to the plane of the naphthalene ring and perpendicular to the best plane of the macroring. In this arrangement, the chiral center of valine, with its substituents, protrudes from one face of the macroring in close proximity to the naphthalene wall protruding from that face. Since (S)-1 contains a C2 axis, complexation from either face produces the same complex. The carboxylate ion formed by the proton transfer from host to guest acts as a counterion for the NH3+ group of the guest, and is centered below the central hole in contact with N+. The arm carrying the carboxylate is of the right length and possesses low energy conformations which would permit the contact ion pair to form. The other arm of
Journal of the American Chemical Society
2830
/
100:9
/
April 26, 1978
Table 1. Enantiomer Distribution Constant (EDC) Estimates in the CDC13-Rich Layer in the Partitioning of an Equivalent of Racemic Host ( H ) and Optically Pure L-Valine as Guest (G) and Their Complexes between Two Liquid Phases Composed from RC02D(H), CDCh. and D70 Host Run Amt, no. Compd mg' 1
2 3 4 5 6 7 8 9
1 1 1 1 1
2 3 4 5
10 11
7 8
12 13 14 15
9 10 11
12
66.4 76.4 70.4 76.4 76.4 98.0 76.0 80.0 66.4 90.0 98.0 80.0 72.0 80.0 78.0
T, "C
Solvents, mL 0.60 0.50 0.55e 0.40' 0.35 0.60 0.65 0.60 0.60 0.50 0.40e 0.60 0.60 0.40 0.50
0.30 0.20 0.40 0.20 1.00."
0.20 0.20 0.24 0.30 0.30 0.30 0.24 0.20 0.20 0.25
0.20 0.10 0.075 0.05 0.25 0.15 0.19 0.21 0.30 0.25 0.14 0.22 0.28 0.15 0.20
Concn ratios at equilibriumb D 2 0 layer, CDCI3 layer, [H]/[G] [G]/[H]
24 0 24 0 24 24 24 24 24 24 24 24 24 24 24
0.5 0.5 0.5 0.45 0.50 0.55 0.40 0.50 0.40 0.42 0.50 0.55 0.60 0.38 0.50
50 1.1 for 24 h. Table I records for runs 1-12 the amounts and kinds of hosts, the amounts and kinds of solvents, the temperatures, the ratios of the concentrations of hosts and guest in the DzO-rich and CDC13-rich layers a t equilibrium, the percents of hosts initially used that were isolated from the D2O-rich layers, and their configurations, percent optical purities, and CRF and EDC values. Rotations taken in CHC13 involved samples of foams dried at 30 'C and 50 p for 24 h was isolated 31 mgof 12, [a]::6+5.0' (c 1.0, CHC13), whichcompares with [a]::6-80.4' (c 1.0, CHC13) for optically pure (R)-l2;4i so the sample was 6% optically pure (S)-12, or 54% (S)-12 and 46% (R)-12, and the C R F was 1.15. From the CDC13-rich layer was isolated 31 mg of 12, [a]::6-5.2' (c 1.0, CHC13). This material was 6% optically pure (R)-12. The total amount of starting host accounted for was -82%. Distribution of Racemic Valine and Optically Pure (8-1 between Two Liquid Phases. Optically pure (S)-14i (0.400 g or 0.602 mmol) was dissolved in 1.O mL of CD3C02D containing 0.177 g (1.5 1 mmol) of racemic valine. Deuteriochloroform (1.5 mL) and D2O (0.50 mL) were added and shaken in a centrifuge tube for 1 min at 24 'C. The
2833 layers were separated (the meniscus was discarded) to give -2.3 mL of the CDC13-rich layer and -0.7 mL of the D20-rich layer. The IH NMR spectra of each phase was then taken. Integrations of the various proton resonances indicated that the D20-rich phase contained only -1% of the total host, and the CDC13-rich phase contained the remaining host plus 1 mol equiv (-40%) of the valine used. The CDCI3-rich phase was evaporated to dryness at
