Enantioselective Recognition of Amino Alcohols and Amino Acids

Abstract

Chiral amino alcohols and chiral amino acids are useful as intermediates for making a variety of biologically active molecules and also as ligands for stereoselective catalysts. Over the years there have been numerous publications on developing receptors for amines, amino acids, and amino alcohols. In most of these studies, molecular recognition is based on noncovalent interactions such as hydrogen bonding, metal coordination, and hydrophobic hydrogen bonding, metal coordination, and hydrophobic interactions. Reversible imine formation has rarely been explored systematically for the recognition studies. When compared to noncovalent interactions, imine bonds are slower to form but have the advantage of being much stronger and structurally well defined. These are features that are particularly desirable for developing stereoselective receptors. We recently showed that resonance assisted hydrogen bonds can greatly increase the rate and equilibrium constants for imine formation. Furthermore, RAHB can orient the imine and restrict its conformational mobility. Here, we compare stereoselective receptors(chiral binol aldehydes) for amino alcohols. ¹H NMR spectrum for (S)-1＇-(3-phenylurylbenzyl)binolaldehyde in benzene-d_(6) containing 5% DMSO-d_(6). Addition of 2-amino-1-propanol to (S)-1＇-(3-phenylurylbenzyl)binolaldehyde results in a rapid decrease in the aldehyde ¹H NMR signal with concomitant increase in the imine signal. ¹H NMR spectrum for a mixture of (S)-1＇-(3-phenylurylbenzyl)binolaldehyde and 2-amino-1-propanol shows the ratio of K_(R)/K_(S). Integration of the two peaks shows that the ratio of R-form/S-form is 1.9:1 at equilibrium. This indicates that the imine formation constant for K_(R) is larger than that for K_(S) by a factor of about 3.7(1.9²). Table 1 shows that (S)-1＇-(3-phenylurylbenzyl)binolaldehyde compares favorably with previously reported receptors for stereoselective recognition of amino alcohols. Furthermore, (S)-1＇-(3-phenylurylbenzyl)binolaldehyde binds all four amino alcohols with the same sense of stereoselectivity. Aside from the RAHB between the phenolic proton and the imine, the alcohol group is within hydrogenbonding distance of the urea group. In the imines formed with (R)-amino alcohols, the imine C-H comes in contact with the hydrogen attached to the chirality center. In the imines formed with (S)-amino alcohols, it is the alkyl or aryl group attached to the chirality center that comes in contact with the imine C-H. The greater steric effect in the (S)-imines appears to be the reason for the greater stability of the (R)-imines. Urea and thiourea groups have recently been shown to be excellent H-bond donors in chiral catalysts. Alanine racemase employs pyridoxal phosphate (PLP) as a cofactor, which reacts with an amino acids to form aldimine intermediate and greatly increase the acidity of the α-proton and induces racemization of L-alanine. The PLP unit is achiral, so it produces only racemic mixture of 50:50% in L-and D-ratio. One of the important features found in alanine racemase is resonance-assisted hydrogen bond (RAHB), which fixes the orientation of imine nitrogen and greatly contributes to increase the acidity of the α-proton. It may be imagined that amino acids would be deracemized by introducing chiral environment around PLP-like unit. In order to realize deracemization, combination of chirality, RAHB and another interaction are required. (S)-1＇-(3-Phenylurylbenzyl)binolaldehyde is a candidate that meets the requisitions. (S)-1＇-(3-Phenylurylbenzyl)binolaldehyde can make aldimine with RAHB, which fixes imine nitrogen toward phenol -OH. RAHB and the hydrogen bonds between carboxylate and uryl -NH groups will fix the whole orientation of the amino acids. This provokes energy difference between the imine of D-alanine and L-alanine bound imines. ¹H NMR for (S)-1＇-(3-phenylurylbenzyl)binolaldehyde in DMSO-d6 shows signals for -OH and two uryl NH protons. These signals disappear with concomitant growing of the peaks corresponding to the imines. ¹H NMR spectra for the imines, (S)-1＇-(3-phenylurylbenzyl)binolaldehyde and DL-alanine in DMSO-d_(6) are significantly different from each other. Receptor (S)-1＇-(3-phenylurylbenzyl)binolaldehyde not only binds to amino acids stereoselectively by imine formation but it also inverts L-amino acids to D-amino acids. In a typical experiment, (S)-1＇-(3-phenylurylbenzyl)binolaldehyde, L-alanine and Et₃N was reacted in DMSO-d6 . A striling result is that L-form changes to D-form as time passes, that is absolute configuration of alanine in the imine is inverted. Right after the addition of triethylamine, the signals corresponding to D-form begin to appear. After 48hrs, the solution reaches to equilibrium where D/L ratio of about 7/1 which is consistent with the magnitude of the stereoselectivity. When the same experiment is carried out with serin, asparaginem tryptophan or histidine, L-epimer is changed into D-epimer and the ratio of D to L is even larger than the case of alanine (Table 1). The ee value of 75 - 90 % is expected for ala, tre, his, ser, tyr. This work shows that the mixing with (S)-1＇-(3-phenylurylbenzyl)binolaldehyde result in deracemization of general amino acids in one step, which does not require enzymes.;광학 활성을 가지고 있는 amino alcohol의 입체 선택적 분리는 중요한 의미를 지닌다. Chiral amino alcohol은 다양한 생활성 분자를 만드는 중간체와 입체 선택적 촉매의 리간드로서 중요한 역할을 하기 때문이다. 최근 몇 년 동안 chiral amino alcohol은 amine, amino alcohol, amino acid를 합성하는 중간체로서 많이 알려지게 되었다. 이들 연구의 대부분은 분자 인식을 수소 결합과 금속배위, 소수성 결합과 금속배위, 소수성 작용과 같은 비공유 상호작용에 기초를 둔다. 비공유 상호작용과 비교할 때 imine결합은 형성되는 것이 느리나, 강력하고 센 구조적 특징으로 많은 이점을 가져온다. 이것은 amino alcohol이 입체 선택적 receptor로서 개발되는데 두드러진 특징이다. Resonance assisted hydrogen bond (RAHB)는 imine형성시에 안정성과 평형상수에 크게 영향을 미칠 것이라고 생각한다. RAHB를 형성한 binol의 proton은 일반적인 수소결합의 proton보다 상대적으로 downfield (>13ppm) 로 이동하고, imine의 위치를 고정시키며 분자 배치의 이동을 제한하는 역할을 한다. 여기에 amino alcohol의 -OH의 oxygen과 binol receptor의 -NH가 가깝게 위치함으로서 수소결합을 형성하여 입체 이성질체의 분자들을 각각 안정한 형태로 분자의 위치를 고정시킨다. 이는 분자모델링 컴퓨터 계산에 의해서 안정한 에너지를 가지는 화합물을 예측할 수 있다. 본 연구에서는 입체 선택적 recepror로서 uryl그룹을 가지는 화합물을 합성하고, 그들과 amnio alcohol과의 입체 선택성에 대하여 고찰하고자 한다.