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Design, Synthesis and Application of Chiral Diamine-based Building Blocks via Diaza-Cope Rearrangement (DCR)

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Authors

권순호

Advisor
김병문
Major
자연과학대학 화학부
Issue Date
2014-02
Publisher
서울대학교 대학원
Keywords
Diaza-Cope Rearrangement/ HPEN / Stereospecific Synthesis / Chiral trans-3-Arylpiperazine-2-carboxylic Acids / Chiral γδ-Diamino Acids / Twinned Alanine Ester / Sugar / Chiral Derivatizing Agent
Description
학위논문 (박사)-- 서울대학교 대학원 : 화학부(유기화학전공), 2014. 2. 김병문.
Abstract
Much interest has been concentrated in the vininal diamine chemistry since many metal-based catalyst and organocatalysts as well as biologically active molecules containing the diamine structure have been synthesized. Diaza-Cope rearrangement (DCR) is a versatile tool for providing a variety of symmetrically-substituted as well as non-symmetrically-substituted chiral vicinal diamines. As the DCR route was introduced, it has rendered the structural tuning and thus electronic diversification of diamino functionality at ease so that many chemists could discover and develop new catalysts and applications owing to the simplicity and effectiveness of the rearrangement. However, use of the DCR for the construction of chiral building blocks for physiologically active molecules or peptidomimetic structures has not been as actively pursued as for catalysts.
The DCR allows for stereospecific synthesis of chiral vicinal diamines through the rearrangement of diimines prepared from 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (hpen) and aldehydes. With a broad perspective, the chiral nonsymmetrical 1,2-disubstituted vicinal diamines could serve as suitable intermediates for the preparation of many physiologically active compounds. Using the hpen as a starting material, a number of useful chiral molecules containing diamine functionality can be synthesized.
Piperazine-2-carboxylic acid has been utilized as an amino acid surrogate in many biologically active compounds. In Chapter 1, the development of an efficient route for enantiopure trans-3-arylpiperazine-2-carboxylic acid derivatives is described though the DCR process. A complete transfer of stereochemical integrity was observed for the transformation. Piperazine ring formation from the chiral 1,2-ethylenediamine derivatives using diphenylvinylsulfonium triflate, followed by oxidation using Ru(III)Cl3•H2O in the presence of NaIO4 provided the desired enantiopure trans-3-arylpiperazine-2-carboxylic acid derivatives.
The rearrangement also allows us to prepare γ,δ-diamino acids, which may be useful for the synthesis of Tamiflu-type antiviral agents as well as various biologically active compounds. In Chapter II, we report the one-pot reaction for the synthesis of γ,δ-diimino esters with two adjacent chiral centers in enantiomerically pure form through DCR of diimines formed from (R,R)-hpen and aldehydes. DFT computation provides interesting understanding into the stereospecific rearrangement reaction. The crystal structure of the product diimine formed from the reaction of (R,R)-hpen and 2,6-dichlorobenzaldehyde shows that the reaction gives the product in S,S configuration.
Preparation of vicinal quaternary carbon centers containing vicinal diamines is synthetically challenging task. In Chapter III, we show that the synthesis of a twinned alanine derivative is efficiently accomplished through the DCR method. Reaction between (R,R)-hpen and methyl pyruvate gives the diaza-Cope rearrangement product with good yield and excellent stereospecificity. The product containing two chiral quaternary carbon centers on vicinal position is characterized by high performance liquid chromatography (HPLC) and X-ray crystallography. DFT computation helps the understanding of why the diaza-Cope rearrangement takes place readily with methyl pyruvate but not with other ketones like acetone and substituted acetophenones.
The structural prevalence of chiral vicinal diamines as versatile chiral building blocks has led to an intense demand of useful tools to simply and inexpensively determine the enantiomeric excess (ee) of the diamine molecules. In Chapter IV, we find that use of sugar molecules such as ribose and arabinose as chiral derivatizing agents is quite efficient in providing good analytical tool to determine the enantiopurities of C2-symmetric vicinal diamines. In this protocol, sugars or diamines do not need to be protected or modified in advance.
Language
English
URI
https://hdl.handle.net/10371/125254
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