以非過渡金屬催化的方式設計合成S-S及C-O鍵與機制探討

Design, Synthesis and Mechanistic Studies to construct S-S and C-O bonds via A Transition Metal Free Approach

吉亞(Jaya Kishore Vandavasi)

指導教授 ： 王志鉦

高雄醫學大學/生命科學院/醫藥暨應用化學研究所/博士(2013年)

摘要

雜環化合物具有相當大的吸引力由於其在天然藥物以及具有生物活性小分子扮演主要的架構，也因此合成多樣性的雜環衍生物在藥物發展中具有十分重要的地位。本文中第一部分我們透過DDQ在溫和的條件下合成非對稱雙硫化合物。此合成路徑簡單、高產率並且適用於多樣性的脂肪族與芳香族硫醇。第二部分，我們合成1,4-oxazine 和1,4-oxazepine衍生物在不需要金屬催化劑以及溶媒條件下並且具有優異的位向選擇性。化合物的立體化學研究也在實驗中被證明。其結果由DFT計算證明。第三部分我們透過hydroalkoxylation反應合成具有indole / pyrrole的1,4-oxazine雜環混成衍生物，令人感到興趣的是在相同的反應路徑下，以propogyl bromide為另一起使物我們可以藉由hydroamination得到azlactone衍生物，此研究的反應機制同樣為DFT計算所證明。第四部分，我們利用過碘化試劑進行hydroalkoxylation 反應去製備對掌性過碘化試劑並用以合成多取代的對掌性morpholine化合物。
參照之前所發表的文獻，以前的合成路徑常常會具有諸多的限制，例如反應需要昂貴的過渡金屬催化、較劇烈的反應，甚或是具有特定官能基的限定。在本論文中，我們藉由S-S和C-X鍵的合成去得到小分子的衍生物藉由較符合環境保護的反應試劑，並且可以較有效率的合成所需的小分子衍生物。

關鍵字

硫-硫鍵生成 ； 碳-氧鍵生成 ； 氫胺化 ； 位向選擇性 ； 立體選擇性 ； 化學選擇性 ； 掌性高價碘

並列摘要

In this thesis, I first report the unsymmetrical disulfide synthesis in the presence of DDQ. A variety of aliphatic and aromatic thiols were employed in the reaction. This procedure is a straightforward manner to give high-product yields. Unsymmetrical disulfides were directly synthesized from the corresponding mixture of thiols in equimolar amounts under mild conditions.
Next, I describe a new approach to construct 1,4-oxazine and 1,4-oxazepine derivatives without solvent and metal. Regioselective cyclization occurred to afford exclusively the exo-dig product, and stereochemistry was studied by circular dichroism and specific optical rotation techniques. The Grignard reaction is a key synthetic step to produce high diastereomeric compounds via the Crams rule; this step was well supported by DFT calculations. A hydroalkoxylation mechanism is proposed and supported by DFT calculations.
In terms of our ongoing work, we have developed the indole and pyrrole conjugate structures with 1,4-oxazines. This method raised the curtain for a new approach to follow hydroalkoxylation reaction without any electron withdrawing group adjacent to alkyne in presence of inorganic base. A new synthetic strategy was developed with catalytic amount of base and the results were supported by DFT calculations. An unusual hydroamination was observed in one-pot, an eco-friendly, and environmental benign with high chemo-, and regioselectivity in presence of base.
We have focused our research with hypervalent iodine reagents to perform hydroalkoxylation. We have synthesized a chiral hypervalent iodine reagent to produce highly substituted chiral morpholines. Development of new chiral reagents is a challenging and most needed process is to beget the chiral molecules.

並列關鍵字

S-S bond formation ； C-O bond formation ； DDQ ； Hydroalkoxylation ； Hydroamination ； Regioselective ； Stereoselective ； Chemoselective ； Chiral PIDA

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