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Stereoconversion of Amino Acids and Peptides in Uryl-pendant Binol Schiff Bases

Title
Stereoconversion of Amino Acids and Peptides in Uryl-pendant Binol Schiff Bases
Other Titles
Uryl작용기를 갖는 Binol Schiff Base를 이용한 아미노산과 다이펩타이드의 입체전환
Authors
박현정
Issue Date
2010
Department/Major
대학원 화학·나노과학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Advisors
김관묵
Abstract
A. Part I : Stereoconversion of Amino Acids and Peptides in Uryl-Pendant Binol Schiff Bases (S)-2-Hydroxy-2’-(3-phenyluryl-benzyl)-1,1’-binaphthyl-3-carboxaldehyde(1) forms Schiff bases with a wide range of nonderivatized natural and unnatural amino acids. Multiple hydrogen bonds, including resonance-assisted ones, fix the whole orientation of the imine and provoke structural rigidity around the imine C=N bond. Due to the structural difference and the increase in acidity of the □ proton of the amino acid, the imine formed with an L-amino acid (1-D-aa) is converted into the imine of the D-amino acid (1-D-aa), with a D/L ratio of more than 10 for most amino acids at equilibrium. N-terminal amino acids in dipeptides are also predominantly epimerized to the D form upon imine formation with 1. Density functional theory calculations show that 1-D-Ala is more stable than 1-L-Ala by 1.64 kcal/mol, a value that is in qualitative agreement with the experimental result. Deuterium exchange of the a proton of alanine in the imine form was studied by ^(1)H NMR spectroscopy and the results support a stepwise mechanism in the L toD conversion rather than a concerted one; that is, deprotonation and protonation take place in a sequential manner. The deprotonation rate of L-Ala is approximately 16 times faster than that of D-Ala. The protonation step, however, appears to favor L-amino acid production, which prevents a much higher predominance of the D-form in the imine. Receptor 1 and the predominant D-form of amino acid can be recovered from the imine by simple extraction under acidic conditions. Hence, 1 is a useful auxiliary to produce D-amino acids of industrial interest by the conversion of naturally occurring L-amino acids or relatively easily obtainable racemic amino acids. B. Part II : Stereoconversion of Dipeptides in the Schiff Bases of Binol Aldehydes with Multiple Hydrogen Bond Donors Novel binol aldehydes derivatized at 2’-hydroxy position with both uryl and acetamide groups (2), and diuryl groups (3) have been synthesized. They were designed for streoselective binding and stereoconversion of general dipeptides with support of multiple hydrogen bonding donor sites in the receptors. The receptors, 2 and 3, converted the chirality of N-terminal amino acids of peptides such as Ala-Gly, Met-Gly, Leu-Gly and His-Gly with stereoselectivity on D-form over L-form. The stereoselectivity ratios were in the range of 5-11, somewhat higher than those of the binol receptor with mono uryl group (1). The DFT calculation at the B3LYP/6-31G*//MPWB1K/6-31G* level revealed that 3-D-Ala-Gly was 2.2 kcal/mol more stable than 3-L-Ala-Gly. The considerable steric hindrance between the methyl group of the alanine and the imine CH moiety of the receptor seems to be the main contributing factor for the thermodynamic preference. C. Part III : Absolute Configuration of Amino Alcohol by Axial Chiral Biphenyl Chiral recognition is particular importance in living systems which often show different activities toward a pair of enantiomeric drugs. 1,2 The chiral recognition phenomena in solution have often been studied by NMR, UV, fluorescence, and circular dichroism spectroscopies. Among them, CD spectroscopy is used routinely in organic chemistry and biochemistry to determine structural differences arising from changes in chirality. A new type of biphenyl, in which 3-phenylurea units are attached to the 2,2’-biphenol group, has been synthesized. It exihibits an axial chirality upon intraction with chiral amino alcohols. Thus, biphenyl is an excellent chirality sensor for amino alcohols. CD spectra obtained from the reactions with different amino alcohols are remarkably similar. The uryl-based receptor showed the same tendency of enantioselectivity toward the chiral amino alcohols. Energy calculation strongly supports complementary hydrogen bonding between alcoholic -OH and uryl two -NHs.;이 논문은 총 3장으로 구성되었다. 제 1장에서는 제일 기본적인 uryl기를 가지는 Binol Schiff base구조를 가지는 화합물을 합성하여, natural amino acids, unnatural amino acids, dipeptides, tripeptide의 L에서 D로의 입체성질을 전환시키는 실험을 하여, 그의 입체 전환선택성을 보았으며, 대부분의 아미노산에서 10:1의 선택비를 가지는 것을 확인하였다. 중수소치환 실험을 통하여 탈수소화, 수소화의 메커니즘으로 아미노산 및 펩타이드의 α-수소의 입체 전환이 이루어짐을 알 수 있었다. 2장에서는 amide와 carboxyl 그룹을 가지고 있는 dipeptide를 binol schiff base 구조에 uryl 그룹이 두개가 연결되어 있는 구조로 되어 있으면, uryl 그룹과 dipeptide 사이의 수소결합이 더욱 강해져 이전의 결과 보다 더 높은 입체 전환 선택성을 가질 것이라 예측하고 실험을 수행하였다. 그러나 실험결과, Binaphthol에 가까이 있는 uryl 그룹만이 dipeptide의 carboxylate 그룹과의 수소결합이 있고, 멀리 있는 uryl 그룹은 dipeptide와의 수소결합이 이루어지지 않음을 확인할 수 있었다. 이는 입체전환 선택성이 uryl 그룹의 수와 상관이 없음을 확인하였으며, 에너지 계산을 통하여 이를 증명할 수 있었다. 3장에서는 Binol Schiff Base와 비슷한 Biphenyl Schiff Base를 만들어, amino alcohol의 키랄성을 쉽게 CD로 측정할 수 있도록 하였다. 대부분의 amino alcohols에 대하여 같은 입체배열을 가지면 비슷한 CD크기와 pattern을 보임을 알 수 있었고, 이를 통하여 amino alcohols에 대한 universal chirality sensor로 응용할 수 있음을 알 수 있었다.
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