N-亞柳胺基酸及N-亞柳胺基四氮唑衍生之掌性氧釩錯合物催化不對稱還原和醛醇加成反應

Chiral Vanadyl Complexs Derived from N-Salicylidene Alpha-amino Carboxylic Acids and Tetrazoles in Asymmetric Reduction and Aldol Reaction

連黛禎(Lian, Dai Jen)

指導教授 ： 陳建添

國立清華大學/理學院/化學系/碩士(2014年)

摘要

以本實驗室先前所開發出的一系列 3,5-雙取代 N-亞柳胺基酸
N-亞柳胺基四氮唑所衍生的氧釩錯合物，與我們發展的 C3 為第三丁基取代，C5 為溴基取代的 N-柳胺基酸所衍生的氧釩錯合物 1a’，應用在催化不對稱還原反應與醛醇加成反應。
在不對稱還原反應中，我們分別利用 C3 為第三丁基取代，C5 為溴基取代的 N-亞柳胺基酸所衍生的氧釩錯合物 1a 與 N-柳胺基酸衍生之氧釩催化劑 1a’，在 -20 oC 下以甲苯為溶劑，還原劑為甲醇修飾後的頻那硼烷，對 α-酮基醯胺衍生物進行不對稱還原反應，可得到產率 62% 與鏡像超越值達 85% 的 R form α-羥基醯胺衍生物。
在不對稱 Mukaiyama 醛醇加成反應中，我們發現 N-亞柳胺基酸氧釩掌性催化劑 1a 搭配具有增加再生轉換效率的三氯乙醇添加劑時，催化 C5 硝基靛紅衍生物及三甲基矽基烯酮縮醛進行不對稱醛醇加成反應效果最理想 (產率 61%， 88% ee)，可得 S form 醛醇加成產物；而利用 C3 為 2,5 –二甲氧基-苯基取代，C5 為硝基取代的 N-亞柳胺酸四氮唑氧釩催化劑 11a 則可得到一系列 R form 的靛紅醛醇加成產物(產率 97%， 90% ee)，推測受質與氧釩配位的最佳構形，具有靛紅之芐基與催化劑 1a 柳醛模板產生 π-π 交互作用以及 C3 第三丁基立體障礙的效應；相反的，受質與催化劑 11a 配位的最佳構形， 具有 C3 2,5-甲氧基-苯基與靛紅之芐基產生另一種 π-π 交互作用可同時避免與四氮唑的電子排斥作用，而生成互補絕對立體化學的產物，我們也利用分子模擬計算催化劑與 N-芐基靛紅配位中間體的最佳構形模型來佐證。

關鍵字

掌性氧釩催化劑 ； 不對稱還原反應 ； 不對稱醛醇加成反應

並列摘要

A series of chiral oxidovanadium (V) methoxides were derived from 3,5-disubstituted-N-salicylidene α-amino carboxylic acids and tetrazoles. These complexes serve as enantioselective catalysts for asymmetric reduction and aldol reaction.
We are the first group that used chiral vanadyl (V) complexes to study the asymmetric reduction. In this study, α-keto amides served as the best substrate class and methanol-modified pinacolborane served as the best reducing agent among five different reducing agents examined. With catalysts 1a (C3 = tBu, C5 = Br) and 1a’ (C3 = tBu, C5 = Br), up to 62% yield and 85% ee (R form) of the α-hydroxyamides were afforded at -20 oC in toluene.
In the past five years, we have already found that chiral vanadyl (V) complexes derived from N-salicylidene α-amino carboxylic acids 1a and tetrazoles 11a (C3 = 2,5-dimethoxyphenyl, C5 = NO2) could achieve complementary asymmetric catalytic aldol processes in addition of silyl ketene acetals (SKA) to isatins at -40 oC in dichloromethane. Herein we further optimized these reactions in the case of 5-nitro-isatin by adding trichloroethanol to facilitate turnover, leading to the corresponding aldol product in moderate yield (61%) and good enantioselectivity (88% ee, S form) with catalyst 1a. Without any additives, using catalyst 11a could furnish a series of R form isatin adducts with up to 97% yield and 90% ee in a complementary manner. Molecular simulations of the adducts between these two catalysts and N-benzylisatin indicated that the preferred coordination mode involve in a facile π-π interaction between the N-benzyl moiety and N-salicylidene template of catalyst 1a to avoid concomitantly the steric hindrance of the C3 tert-butyl. On the other hand, another π-π interaction between the C3 2,5-dimethoxylphenyl group of catalyst 11a and the N-benzyl group of the isatin to avoid concomitantly the el-el repulsion with the tetrazole moiety is involved, leading to a complementary, enantiofacial exposure of the carbonyl moiety in the N-benzylisatin.

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