Piperidine과 그 유도체들의 산화성 전이반응에 관한 연구

허완 단국대학교 대학원 1997 국내석사

Piperidine과 그 유도체들의 N-oxide를 얻기 위하여 저온인 0℃∼-78℃에서 오존반응을 실시하였다. Piperidine N-oxide는 즉시 전이반응을 하여 N-hydroxylpiperidine형태도 생성됨이 관찰되었다. 그러나 N-methylpiperidine, N-tert-butylpiperidine과 같이 질소에 alkyl기가 치환된 화합물에서는 olefin형태의 화합물이 생성되는 pyrrolidine 경우와는 달리 전이반응이 일어나지 않았다. 이것은 alkyl group이 equatorial위치로 존재하고, N-alkylpiperidine이 안정한 6각구조를 이루기 때문이다. 따라서 N-oxide는 상온에서 axial위치로 존재했고, 이때에 높은 수득률을 보였다. In order to the obtain piperidine and its derivatives N-oxides, ozonolysis was conducted at low temperature between -78℃ and 0℃. It was observed that piperidine N-oxide formed was immediately rearranged to give N-hydroxylpiperidine. However, N-alkylated compound such as N-methylpiperidine and N-tert-butylpiperidine were not rearranged to form olefin compounds which were obtained in case of pyrrolidine, probably because alkyl group in N-alkylpiperidine can exist at equatorial position with stable six-membered ring. Accordingly, N-oxide occupies axial position at room temperature and yield was high.

Part A. Piperidine이 도입된 sphingoid base analogue의 설계 및 합성 연구 Part B. 신규한 heterocalixarene인 calixtriazole의 합성과 그 유용성 검증 연구

조지희 서울대학교 대학원 2012 국내박사

Part A: Piperidine이 도입된 sphingoid base analogues의 설계 및 합성 연구 Sphingolipid는 모든 진핵 세포에서 발견되며 주로 plasma membrane에 존재하여 구조적인 역할을 담당하고 있다. 구조적 기능에 추가적으로 세포 내 중요한 생리활성 작용에 관여하는 것으로 알려져 있는 sphingolipid는 이러한 특성 때문에 많은 화학자들 사이에서 natural 및 non-natural sphingolipid 유도체들의 합성이 다양하게 수행되고 있다. 특히, sphingolipid 합성에 있어서 가장 중요한 부분 중 하나는 sphingolipid의 기본 골격인 sphingoid base를 합성 하는 것이라 볼 수 있다. 본 논문은 sphingolipid의 기본 골격인 sphingoid base의 2-amino group과 C-4 carbon atom 사이에 cyclic moiety가 도입되어 구조의 일부가 constrained된 sphingoid base analogue의 효과적인 합성방법을 제시하고자 하는 논문이다. Piperidine이 도입된 sphingoid base analogue의 기본골격 합성을 위한 주요반응으로 tandem enyne/diene-ene metathesis를 수행하였으며, 이를 통해 합성된 diene moiety를 이용하여 입체선택적인 일련의 반응들을 진행함으로써 piperidine이 도입된 sphingoid base analogue들을 성공적으로 합성할 수 있었다. 합성된 sphingoid base analogue들의 기본적인 biological evaluation 수행 결과, constrained된 sphingoid base analogue들이 기존의 proto type natural sphingoid base보다 cancer cell의 증식을 훨씬 더 효과적으로 억제함을 관찰할 수 있었으며, 이를 통해 sphingolipid의 생체 내 활성 연구에 있어 새로운 화학적 도구로서의 개발 가능성을 제시하였다. Part B: 신규한 heterocalixarene인 calixtriazole의 합성과 그 유용성 검증 연구 Calixarene은 거대고리 화합물로서 그들만이 가지는 구조적인 특이성과 적당한 작용기를 접목시킬 수 있는 lower rim과 upper rim으로 인하여 다양한 분자를 선택적으로 인식할 수 있는 장점을 가지고 있다. 이에 따라 calixarene 화합물을 이용하여 특정 분자에 대한 선택성과 결합 매커니즘을 밝히려는 연구가 전 세계적으로 활발히 진행되고 있다. 그러나 calixarene의 구조변환 및 작용기의 접목에는 제한이 있기 때문에 calixarene을 이용한 분자인식 연구에는 한계성이 존재한다. 본 논문은 calixarene의 이러한 한계성을 개선하고자 calixarene의 phenol 구조가 1,2,3-triazole로 변환된 calixtriazole을 합성하고, 합성된 calixtriazole의 구조적 특성 및 새로운 유기 리간드로서의 기능을 규명하고자 하는 논문이다. Calixtriazole의 합성을 위한 주요반응으로 copper(I)-catalyzed Huisgen 반응을 이용하였으며, stepwise와 one-pot의 2가지 반응경로를 통해 효과적으로 합성하였다. 합성된 calixtriazole의 구조적 특성은 다양한 분광학적 분석방법 및 computational study를 통해 연구되었으며, pyrene이 도입된 calixtriazole을 합성하여 여러 양이온 중 특정 양이온에 대한 선택성을 가짐을 확인할 수 있었다. 이러한 연구결과를 바탕으로 합성된 calixtriazole이 기존의 calix[4]arene과는 다른 독특한 특성을 가지는 새로운 heterocalixarene임을 증명할 수 있었다. Part A. Design and Synthesis of Piperidine-Containing Sphingoid Base Analogues We report an approach that allows the efficient synthesis of the designed sphingoid base analogues in which the conformational restriction is introduced by incorporation of a cyclic moiety between the 2-amino group and the C-4 carbon atom of the sphingoid base. Our synthesis features a tandem enyne/diene-ene metathesis reaction that provides access to the designed framework. The diene moiety of the metathesis product is stereoselectively elaborated for the synthesis of the designed analogues. The preliminary biological evaluation indicates that the designed constrained analogues are much more effective than prototype natural sphingoid bases at inhibiting cancer cell growth. Part B. Synthesis and Evaluation of Calixtriazoles as a New Class of Hybrid Heterocalixarenes The interesting physicochemical properties of 1,2,3-triazole and the distinct shape of calixarenes are combined in calix[2]triazole[2]arene, a new template molecule that can be used in supramolecular chemistry. The assembly of the two triazoles and the macrocycle was achieved via a copper(I)-catalyzed Huisgen reaction in both stepwise and one-pot procedures. The conformational features were examined by the computational, NMR spectroscopic, and X-ray structures. Pyrenyl derivatives of the calix[2]triazole[2]arene displayed excellent selectivity for specific metal ions and provided insights into the distinctive properties of calix[2]triazole[2]arenes relative to calix[4]arene.

Synthesis and evaluation of calixtriazoles as a new class of hybrid heterocalixarenes (Part B)

조지희 서울대학교 대학원 2012 국내박사

Styryldiphenylphosphine oxide 誘導體에 대한 Piperidine의 親核性 添加物의 合成

이진규 高麗大學校 1986 국내석사

(A) multi-method approach to analyzing O-GlcNAc modified peptides

방미라 서울대학교 대학원 2017 국내석사

The O-linked β-N-acetyl glucosamine (O-GlcNAc) modification, a dynamic post-translational modification (PTM) to serine or threonine residues of nuclear and cytoplasmic proteins from almost all functional classes, is involved in many different cellular processes including signal transduction, protein degradation, and regulation of gene expression. O-GlcNAc modification is known to be associated with several human disease states, such as diabetes, cancer, cardiovascular and neurodegenerative disorders. Despite the vital functional roles of protein O-GlcNAcylation in many cellular processes, the area of O-GlcNAc research field has been hampered, mainly due to the lack of techniques for the identification, quantification and site mapping of O-GlcNAc modification in proteins. Proteomic analysis of O-GlcNAc modified proteins still presents significant challenges following reasons. First, site mapping of O-GlcNAcylation is very difficult due to its collision-induced dissociation (CID)-labile β-linkage between O-GlcNAc moiety and serine or threonine residues. Second, O-GlcNAc modified proteins are present in low stoichiometry at each site on proteins. Therefore, the research of O-GlcNAc modification has been limited by difficulties in mapping sites of O-GlcNAc modification. In this study, a new multi-method approach is introduced using enrichment and novel N-terminus tag based on the application of CID tandem mass spectrometry for O-GlcNAc proteome profiling. To compensate the substoichiometric occupancy and the lability of O-GlcNAc modified proteins, a new method for enrichment and detection is developed. The approach is combined with (i) lectin weak affinity chromatography (LWAC) and (ii) TEMPO [2-(2,2,6,6-tetramethyl piperidine-1-oxyl)]-assisted free radical-initiated peptide sequencing mass spectrometry (FRIPS MS). Collectively, with combined with LWAC and TEMPO-assisted FRIPS MS, this approach can be used in a variety of applications for O-GlcNAc research, all of which will provide insights into the many functions of O-GlcNAcylation in biological systems. The approach is not only improving enrichment for O-GlcNAc modified peptides but also allowing confirmation of a number of O-GlcNAcylation sites. We envisage that further application of the method to biological systems, which will elucidate the mechanism of specific role of protein O-GlcNAcylation in many biological processes. The new multi-method provides an ideal platform to profile global O-GlcNAc peptides for quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and will enable the study of functional roles of O-GlcNAc modified peptide in biological systems.

Prins-type cyclization을 이용한 2,4,6-Trisubstituted tetrahydropyrans의 입체선택적 합성 연구

김영습 高麗大學校 大學院 2012 국내석사

Abstract Young Seub Kim Dept. of Chemistry The Graduate School Korea University I. Synthesis and Biological Evaluation of Quinuclidine, Pyrrolidine and Piperidine Derivatives as Potential Therapeutic Agents for Alzheimer’s Disease. Alzheimer’s disease (AD) is a progressive neurological disorder characterized by impairment of memory and cognitive decline. Accounting for more than 20 million cases worldwide, AD is both the most common neurodegenerative disorder and the most prevalent form of dementia. The disease is estimated to currently affect three to four million people in the United States, and its prevalence is increasing as a greater proportion of the population reaches a longer life expectancy. Although the etiology of AD is unknown, histopathological hallmarks such as amyloid ß(Aß) deposits, τ-protein aggregation, oxidative stress and low levels of acetylcholine(Ach) have been characterized. Recently, it was reported that Dimebon, clinically used as an antihistaminic drug in Russia since 1983, exhibited neuroprotective effects along with cognition enhancing effects in clinical trials. It appears to operate through multiple mechanisms of action including blockade of mitochondrial permeability transition pores (mPTP), which is considered as a main effective target for treatment of AD. In this study, we have synthesized and biologically evaluated quinuclidine, pyrrolidine and piperidine derivatives as potential mPTP blockers. We have identified several compounds showing high inhibitory activity against Aß induced mitochondrial depolarization in HT-22 cell. As a result, we have found KKSM02008, a quinuclidine deriviative, showed relatively high activity in JC-1 HTS assays. In addition, KKSM02008 exhibited great stability in rat plasma and human hepatic microsomes. However, it did not recover the memory impairment induced by Aß in the rat behavior experiment. In the case of piperidines and pyrrolidine derivatives, we found that KKSM02048 has good in-vitro assay profile in the ATP production and MTT toxicity tests as well as JC-1 assay. Further investigation of KKSM02048 on pharmacological experiments such as in vitro stability test and PK experiment is currently in progress.   Abstract Young Seub Kim Dept. of Chemistry The Graduate School Korea University Ⅱ. Stereoselective Synthesis of 2,4,6-Trisubstituted Tetrahydropyrans via Prins-type Cyclization Functionalized oxacyclic compounds such as tetrahydrofurans or tetrahydropyrans constitute key structural motifs of a large number of biologically active natural products. One of the efficient synthetic strategies to synthesize these types of heterocycles is Prins cyclization methodology, that is, an intramolecular electrophilic addition of double bond to oxocarbenium ion intermediate. An effective and stereoselective synthesis of 2,4,6-trisubstituted tetrahydropyrans is described. The reaction of 2-methylene-1,4-diol with aromatic aldehydes in the presence of TMSOTf gave the 3 : 1 mixture of 2-aryltetrahydropyran-4-carbaldehyde. However, the use of benzaldehyde dimethyl acetal led to 2,4-disubstitued tetrahydropyran having dimethylacetal at the 4 position with high diastereoselectivity (>12:1). By applying this reaction to 3-methylene-1-phenylbutane-1,4-diol, we finally were able to synthesize 2,4,6-trisubstitued tetrahydropyrans (2,6-cis and 2,4-syn) in good to moderate yields.

Enantioselective synthesis of piperidine and isoindolizidine derivatives

Piao, Fengnu Graduate School, Yonsei University 2012 국내석사

Piperidine and benzoindolizidine derived heterocyclic scaffolds are ubiquitous, and represent a unique class of heterocyclic compounds in terms of biological and pharmacological features. Enantioselective synthesis to obtain optically pure piperidine and benzoindolizidine derivatives are interesting area in organic synthesis. The interests in piperidine and benzoindolizidine alkaloids are well showed by the variety of published material and biological activities. Accordingly, numerous methods have been developed for the enantioselective synthesis of substituted piperidines and benzoindolizidines continues unabated. Although there are several reports on asymmetric synthesis of diversely substituted piperidine and benzoindolizidine derivatives, general and reliable methods are still in demand. In this context, we have developed a highly enantioselective method for the synthesis of piperidine and benzoindolizidine derivatives by employing a strategy of asymmetric allylation in the presence of a organocatalyst, cleavage of N-N bond, N-allylation and the ring closing metathesis. The reaction furnished an access to several highly enantioenriched piperidine and benzoindolizidine motifs in high yields. To illustrate more utility of this methodology, synthesis of piperidine alkaloid, (S)-(+)-coniine, isoindolinone, (S)-PD 172938 have been demonstrated.

CO2 Absorption Characteristics of Aqueous Amine Solutions with Piperidine Derivatives as Promoters

Lee, Yong Woon 고려대학교 대학원 2015 국내석사

The increase of greenhouse gas emission on account of increasing use of fossil fuel after the Industrial Revolution has caused global warming, which has had much influence on human ecosystem. In order to reduce carbon dioxide, which makes up most of the greenhouse gas, many technologies are applied. Among those, Carbon Capture & Storage (CCS) technology comes to the fore to reduce mass carbon dioxide. As carbon capture technology among CCS technologies comprises 75~85% of the cost, it is very important to develop a new technology to decrease the capturing cost. Chemical absorption method using amine absorbent is coming close to commercialization, for which a lot of researches are currently being conducted. In particular, they develop the technology to reduce capturing cost by decreasing thermal energy used for processes by improving the performance of amine mainly in the advanced countries. This study aims to improve the performance of absorption tower by improving absorption rate of amine absorbent. In order to achieve the goal, we have studied the absorption rate improvement effect of using Piperidine(PD), which has more improved performance than Piperazine(PZ) which has been used for absorption rate improver. Wetted Wall Column(WWC) was used for measuring absorption rate of absorbent as the experiment equipment for evaluating CO2 absorption characteristics of the improved absorbent, and Continuous Stirred Tank Reactor(CSTR) was used for measuring absorption performance. In order to compare CO2 absorption rate, overall mass transfer coefficient (KG) was found at 40℃ by using WWC equipment. In addition, in order to compare CO2 cyclic capacity was found by using the difference between Rich-CO2 Loading and Lean-CO2 Loading with 40℃ of absorption tower temperature as Rich-Loading and 90℃ of stripper tower temperature as Lean-CO2 Loading by using CSTR. To review the influence on the absorption rate improvement according to the position of substituent of PD derivatives, 1-Methylpiperidine(1-MPD), 2-Methylpiperidine(2-MPD), 3-Methylpiperidine(3-MPD) and 4-Methylpiperidine(4-MPD), which are the methylpiperidine derivatives, were chosen in this study. As a result of the experiment, the CO2 absorption rate was found to be the fastest of KG value when methyl group existed at Para position, and KG value decreased as methyl group got closer to amine group of PD. As for CO2 cyclic capacity increased due to steric hindrance effect as substituent of Methyl-PD derivatives got to close to amine group. Cyclic capacity was the highest when methyl group exited at ortho position. In addition, after comparing CO2 absorption characteristics according to the type of substituents using PD derivatives which have Hydroxyl group as a 4-Hydroxylpiperidine(4-HPD). 4-HPD had rate improvement effect as rate promoter, but the rate promoter effect was lower than 4-MPD. However, hydroxyl group increased CO2 dissolution nature and improved absorption performance. When adding 4-MPD rate promoter in tertiary amine which is advantageous for regeneration, excellently complemented absorbents can be developed from the aspects of CO2 absorption rate, absorption performance, properties and recycled energy.

2,2,6,6-Tetramethy1-1-piperidine oxoammonium ion을 이용한 1-monocaprin내 1차 알코의 선택적 산화 : Selective Oxdation of Primary Alcohol Group in 1-Monocaprin Mediated by 2,2,6,6-Tetramethy1-1-piperidine oxoammonium ion

임혜경 서울産業大學校 産業大學院 2006 국내박사

본 논문에서는 TEMPO/hypobromite sodium/sodiumbromide을 촉매로 사용하여 1-monocaprin의 1차 alcohol group을 25℃ pH 10.8 에서 산화반응 시키되, 2차 alcohol group의 산화 없는 선택적 산화를 수행하였다. 물에 대한 용해도와 분산성은 산화된 1-monocaprin이 산화되지 않은 1-monocaprin에 비해 각각 80배 및 9배 수준으로 더 높았다. 또한 산화된 1-monocaprin의 ESI(emulsion stability index)는 초기 1-monocaprin보다 높은 값을 가지되, 선택적으로 산화된 1-monocaprin이 포함된 emulsion은 특히 수분이 90%수준인 조건을 가장 선호하며, 반면에 산화 않된 1-monocaprin은 수분이 40% 수준인 조건을 가장 선호하는 것으로 판명되었다. 이러한 결과는 1차 alcohol이 선택적으로 산화된 1-monocaprin의 친수성이 증가하는데 기인을 하는 것으로 생각되며, 결과적으로 산화된 1-monocaprin은 산화되지 않은 1-monocaprin보다 물에 안정 하다는 것을 알 수 있었다. IR spectra와 ^(13)C-NMR에서는 각각 1,600 cm^(-1) 분광에서의 peak와 175 ppm부근에서의 peak를 확인함으로써 1차 alcohol만이 carboxyl group으로 전환되었음을 입증할 수 있었다. Primary alcohol group of 1-monocaprin was selectively oxidized using TEMPO/sodium hypochlorite/sodium bromide as a catalyst at 25℃ and pH 10.8, without oxidation of secondary alcohol group. Water solubility and dispersibility of oxidized 1-monocaprin were higher than those of unoxidized 1-monocaprin by about 80 times and 9 times, respectively. Also, ESI (emulsion stability index) of oxidized 1-monocaprin was higher than that of unoxidized 1-monocaprin. Emulsion which contains selectively oxidized 1-monocaprin liked 90% of water however unoxidized 1-monocaprin liked 40% of water. The result showed that carboxylic acid in selectively oxidized 1-monocaprin contributed to increase hydrophilic property. Emulsion formed by oxidized 1-monocaprin was more stable than that by unoxidized 1-monocaprin in the water high region. It was found out that only primary alcohol group in 1-monocaprin was converted to carboxyl group, by confirming the peak of IR spectra at 1,600 cm^(-1) and the peak of ^(13)C-NMR at 175 ppm.

立體選擇的인 反應을 利用한 α-Conhydrine의 全合成

허성일 성균관대학교 일반대학원 2011 국내석사

α-Conhydrine은 Piperidine Alkaloid로써 Conium maculatum과에 속하는 Hemlock에서 추출할 수 있는 식물성 alkaloid이다. Hemlock은 강한 독성을 갖고 있는 생리활성 물질로서 glycosidase inhibitor, antiviral, antitumor의 활성을 갖고 있기 때문에 immunomodulators, 항암제, 항바이러스제, 항박테리아제 또는 당뇨병의 치료제로서의 역할이 가능하다. 우리는 Stereo selectivity를 이용하여 amino ketone에서 anti-amino alcohol로 입체선택 적인 합성을 하고 Grubbs` first-generation catalyst에 의한 Ring Closing Metathesis 반응을 통하여 carbon chain을 차이를 이용하여 5원환 반응과 6원환 반응으로 만들어 선택적으로 Piperidine Alkaloid 와 endopeptidase inhibitor의 역할이 가능한 Pyrrolidine Alkaloid의 azasugar 유도체의 합성이 가능한 방법을 선택하였다. 이러한 접근 방법은 응용에 따라서 다양한 Ring size의 합성이 가능할 것이라 예상 된다. Conhydrine is one of the alkaloids of the hemlock, isolated from the seeds and leaves of the poisonous alkaloids plant Conium maculatum L, whose extracts were used in the ancient Greece for execution of criminals. On the other hand, it was used for nerve pain and asthma drugs. Also, Biologically active alkaloids containing 2-(1hydroxyalkyl)- piperidine unit are abundant in nature and have attracted much attention due to their antiviral and antitumor properties. This compound includes (+)-a-conhydrine which was first isolated from the seeds and leaves of the poisonous plant, Conium maculatum L, in 1856. Various methods for the asymmetric synthesis of α-conhydrine have been documented in the literature. In former times elegant approaches give (+)-α-conhydrine in good overall yield but are limited by access to structural analogues. We believe that a range of analogues with varying ring sizes can be easily accessed using our approach. In our approach for the synthesis of α-conhydrine, a key step is highly diastereoselective reduction of the amino ketone to give the anti-amino alcohol directly and ring-closing metathesis by Grubbs` first-generation catalyst.