臺灣博碩士論文加值系統

本論文主要探討酮類化合物及不同烯類之有機催化Michael加成反應，以吡咯啶－樟腦衍生之有機催化劑進行反應，得到具有高產率及高立體選擇性之Michael加成產物，內容共分成三部分予以探討。
第一章：不對稱合成之簡介
此章節介紹了掌性的概念，及文獻中以不對稱合成方法製備掌性分子的整理，其中針對不同類型及活化方式的有機催化發展做深入的探討。
第二章：酮類化合物對alkylidene malonates的Michael加成反應
本實驗中，以吡咯啶－樟腦衍生之有機催化劑，有效進行酮類化合物對alkylidene malonates的Michael加成反應，得到相對應的Michael加成產物，有高達95%的產率，非鏡像選擇性大於99% de，及最高96% ee的鏡像選擇性；生成的Michael加成產物亦可藉由化學反應，轉換成掌性的內酯，且不影響其立體選擇性。
第三章：藉由Michael加成反應進行3-nitro-2H-chromene的光學分割
以吡咯啶－樟腦之衍生物，做為雙功能有機催化劑，醋酸為添加劑，在無溶劑、0 oC的反應條件下，進行外消旋之2-aryl-3-nitro-2H-chromene的光學分割。大致上，酮類化合物與外消旋之2-aryl-3-nitro-2H-chromene的Michael加成反應，均可順利得到高產率及高立體選擇性的Michael加成產物(最高產率47%，非鏡像比例92：8，93% ee)；而經由光學分割後，回收之起始物chromene也有高達42%的產率及72% ee的鏡像選擇性。

The research work presented in this dissertation is highlighting the organocatalysed Michael addition reactions of ketones to various electron deficient activated olefins. The pyrrolidinyl-camphor derived catalysts were shown good results in the Michael addition reactions in terms of chemical yield and stereoselectivities of the Michael adducts. Thesis is divided into three chapters as mentioned below.
Chapter 1. General Introduction: Asymmetric synthesis
This chapter deals with the origin and importance of “chirality” in nature and human life. Brief introduction towards asymmetric synthesis of chiral molecules and their importance in pharmaceutics. The development and classification of organocatalysis.
Chapter 2. Asymmetric Michael addition of ketones to alkylidene malonates.

In this part we have been developed the enantioselective Michael addition of ketones to the alkylidene/arylidene malonates. Pyrrolidine-camphor derivative (39e) was found to be efficient catalyst for the enantioselective conjugate addition of ketones to the alkylidene malonates to give the corresponding products (36a-n and 40b-g) in high yields ( up to 95%) with high diastereo-selectivities (up to >99) and enantioselectivities (up to 96%). The Michael adducts obtained can be easily transformed into the chiral lactones (41a) without any discrimination in stereoselectivities.
Chapter 3. Kinetic resolution of 3-nitro-2H-chromenes via organocatalysed Michael addition.
Kinetic resolution of racemic 2-aryl-3-nitro-2H-chromenes (56a-l) has been explored with the pyrrolidinyl-camphor derivative 57b as a bifunctional organocatalyst under neat conditions in the presence of AcOH at 0 oC. In general, the organocatalytic asymmetric Michael addition of ketones proceeded smoothly to give the functionalized Michael adducts (58a-n) with good to high diastereo- and enantioselectivities (up to 92:8 dr, 93% ee, and 47% yield). The less reactive chromenes (S)-56a-h, k, l and (R)-56i-j were recovered in high chemical yields and moderate optical purity (up to 42 % chemical yield and 72% ee).

Contents
Abstract…………………………………………………………………………………………………………………………………i Contents…………………………………………………………………………………………………………………………iv
Abbreviations………………………………………………………………………………………………………………………v
1. General Introduction……………………………………………………………………………………………………..1
1.1. Chirality……………………………………………………………………………………………………………………1
1.2. Asymmetric organocatalysis…………………………………………………………………………………….2
1.3. Covalent catalysis……………………………………………………………………………………………………5
1.3.1. Amine catalysis……………………………………………………………………………………………..6
1.3.2. Nucleophilic catalysis…………………………………………………………………………………..13
1.4. Non-covalent catalysis………………………………………………………………………………………….14
1.4.1. Hydrogen bonding catalysis………………………………………………………………………..14
1.4.2. Phase transfer catalysis……………………………………………………………………………….15
1.5. Bifunctional catalysis…………………………………………………………………………………………….16
1.6. References……………………………………………………………………………………………………………16
2. Asymmetric Michael addition of ketones to the alkylidene malonates……………………..21
2.1. Introduction: Michael addition……………………………………………………………………………..21
2.2. Results and discussion………………………………………………………………………………………….28
2.3. Conclusions…………………………………………………………………………………………………………..35
2.4. Experimental section…………………………………………………………………………………………….35
2.5. References…………………………………………………………………………………………………………….51
3. Kinetic resolution of racemic 2-aryl-3-Nitro-2H-chromenes Via
organocatalysed Michael addition………….………………………………………………………………..55
3.1. Introduction…………………………………………………………………………………………………………55
3.1.1. Kinetic resolution………………………………………………………………………………………55
3.1.2. Chiral chromenes and chromans……………………………………………………………….61
3.2. Results and discussion………………………………………………………………………………………….64
3.3. Conclusions…………………………………………………………………………………………………………..72
3.4. Experimental section………………………………………………………………..…………………………..72
3.5. References…………………………………………………………………………………………………………….95

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18. For selected references on organocatalysed oxa-Michael-Aldol reaction see: a) B. C. Das, S. Mohapatra, P. D. Campbell, S. Nayak, S. M. Mahalingam, T. Evans, Tetrahedron Lett. 2010, 51, 2567; b) D.-Q. Xu, Y.-F. Wang, S.-P. Luo, S. Zhang, A.-G. Zhong, H. Chen, Z.-Y. Xu, Adv. Synth. Catal., 2008, 350, 2610; c) T. Karthikeyan, S. Sankararaman, Tetrahedron: Asymmetry, 2008, 19, 2741; d) R. Rios, H. Sundén, I. Ibrahem, A. Córdova, Tetrahedron Lett. 2007, 48, 2181; e) H. Li, J. Wang, T. E. Nunu, L. Zu, W. Jiang, S. Wei, W. Wang, Chem. Commun. 2007, 507; f) W. Wang, H. Li, J. Wang, L. Zu, J. Am. Chem. Soc. 2006, 128, 10354; g) T. Govender, L. Hojabri, F. M. Moghaddam, P. I. Arvidsson, Tetrahedron: Asymmetry 2006, 17, 1763; h) H. Sundén, I. Ibrahem, G.-L. Zhao, L. Eriksson, A. Córdova, Chem. Eur. J. 2007, 13, 574.
19. For selected references on organocatalyzed synthesis of chiral chromans see: a) D. B. Ramachary, M. S. Prasad, R. Madhavachary, Org. Biomol. Chem. 2011, 9, 2715; b) B.-C. Hong, P. Kotame, J.-H. Liao, Org. Biomol. Chem. 2011, 9, 382; c) L. Zu, S. Zhang, H. Xie, W. Wang, Org. Lett. 2009, 11, 1627.
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22. a) C. Chang, S.-H. Li, R. J. Reddy, K. Chen, Adv. Synth. Catal. 2009, 351, 1273; b) R. J. Reddy, H.-H. Kuan, T.-Y. Chou, K. Chen, Chem. Eur. J. 2009, 15, 9294; c) D. R. Magar, C. Chang, Y.-F. Ting, K. Chen, Eur. J. Org. Chem. 2010, 2062; d) Y.-F. Ting, C. Chang, R. J. Reddy, D. R. Magar, K. Chen, Chem. Eur. J. 2010, 7030.
23. Detailed X-ray crystallographic data are available from the CCDC, 12 Union Road, Cambridge CB2, 1EZ, UK (www.ccdc.cam.ac.uk/data_request/cif) for chroman derivative 58a (CCDC No. 848085).