Bicyclic guanidine catalyzed enantioselective isomerization reactions

BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ISOMERIZATION REACTIONS LIU HONGJUN NATIONAL UNIVERSITY OF SINGAPORE 2010 BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ISOMERIZATION REACTIONS LIU HONGJUN 2010 BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ISOMERIZATION REACTIONS LIU HONGJUN (BSc., Nankai University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2010 To my parents, sisters, and Wei-Tian, for their love, support, and encouragement Acknowledgements First and foremost, I would like to take this opportunity to thank my supervisor, Associate Professor Tan Choon-Hong, for his guidance and encouragement throughout my PhD research and study. I appreciate Ms. Loh Wei-Tian’s help in proofreading this manuscript. I would like to thank all my labmates for creating such a harmonious, encouraging, and helpful working environment. My special thanks go to Mr. Dasheng Leow for his great contribution to the isomerization project. I would also like to thank Mr. Yuanhang Pan for his participation in oxidative cyclization project, Mr. Wei Feng for his help on tandem isomerization-Michael project, Dr. Jiang zhiyong and Mr. Fu Xiao for their kindly discussion throughout my research. I thank Mdm Han Yanhui, Miss Ler Peggy and Mr. Wong Chee Ping for their assistance in NMR analysis, and Mdm Wong Lai Kwai and Mdm Lai Hui Ngee for their assistance in Mass analysis as well. I also owe my thanks to many other people in NUS chemistry department, for their help and assistance from time to time. Last but not least, I thank all my friends in Singapore who helped me settle down at the beginning. Singapore is a great place and I enjoy the life here. Table of Contents Summary List of Schemes List of Tables List of Figures List of Abbreviations Chapter Chiral Guanidines and Guanidinium Derivatives as Asymmetric Catalysts---------- 14 Chapter Enantioselective Synthesis of Isomerization of 3-Alkynoates Chiral Allenoates by Guanidine-Catalyzed 2.1 Introduction to Enantioselective Synthesis of Axial Chiral Allenes-------------34 2.2 Enantioselective Synthesis of Chiral Allenoates by Guanidine-Catalyzed Isomerization of 3-Alkynoates------------------------------------------------------- 39 2.3 Application and Chirality Transfer for Chiral 3-Allenoates---------------------- 51 Chapter Brønsted-Base Catalyzed Tandem Isomerization-Michael Reactions of Alkynes 3.1 Introduction to the Synthesis of 2-Alkylidenetetrahydrofurans------------------59 3.2 Brønsted-base catalyzed tandem isomerization-oxy-Michael reactions of alkynes: a novel method for synthesis of 2-alkylidenetetrahydrofurans------------------ 63 3.3 Brønsted-base catalyzed tandem isomerization-aza-Michael reactions of alkynes: the synthesis of azacycles------------------------------------------------------------- 69 3.4 Unsuccessful Concepts for Brønsted-base Catalyzed Tandem Isomerization-Michael Reactions---------------------------------------------------- 74 Chapter Bicyclic Guanidine Catalyzed Asymmetric Tandem Mannich-Isomerization Reactions 4.1 Discovery of Tandem Mannich-Isomerization Reactions------------------------- 78 4.2 Development of Enantioselective Tandem Mannich-Isomerization Reactions- 80 Chapter Experimental Procedures 5.1 General Procedures and methods----------------------------------------------------- 86 5.2 Preparation and Characterization of Substrates and Products-------------------- 89 Appendix-------------------------------------------------------------------------------------- 121 Publications----------------------------------------------------------------------------------- 192 Conference presentations------------------------------------------------------------------ 193 Summary The aim of this study is to develop highly enantioselective isomerization reactions catalyzed by chiral bicyclic guanidines. A chiral bicyclic guanidine was found to catalyze the isomerization of alkynes to chiral allenes with high ees. The axial chirality was efficiently transferred to functionalized butenolides and cycloaddition products. We have also successfully demonstrated the stereospecific synthesis of butenolide through allenoate cyclization with a catalytic cationic Au(I) complex. A possible mechanism has been proposed to explain the enantioselective isomerization reaction. We have also found that a Brønsted-base catalyzed tandem isomerization-Michael reaction can be used to form useful heterocycles under mild conditions. This efficient method was applied 2-alkylidenetetrahydrofurans isomerization-aza-Michael to the synthesis with reaction with of various excellent alkynyl-amines, yields. functionalized Tandem alkynyl-amide and alkynyl-carbamates led to interesting piperidines, lactams and oxazolidinones. Asymmetric version of tandem isomerization-aza-Michael reaction was tested to give moderate ee using a chiral bicyclic guanidine as a catalyst. We have discovered a Brønsted-base catalyzed tandem Mannich-isomerization reaction between imines and itaconimides. Moderate to good ees were achieved with this reaction catalyzed by a chiral bicyclic guanidine. List of Schemes Scheme 1.1 Henry reaction catalyzed by homochiral guanidine. Scheme 1.2 Lipton’s cyclic dipeptide catalyzed Strecker reaction. Scheme 1.3 Ma’s chiral guanidine catalyzed Michael reaction. Scheme 1.4 Ishikawa’s chiral guanidine catalyzed Michael reaction of glycinate. Scheme 1.5 Enantioselective Mannich reactions of various N-Boc protected imines catalyzed by guanidine ent-22a. Scheme 1.6 Guanidine ent-22d catalyzed intramolecular oxa-Michael cyclization reaction. Scheme 1.7 Monocyclic Guanidine promoted epoxidation. Scheme 1.8 Chiral guanidine 38 catalyzed borane reduction of phenacyl bromide. Scheme 1.9 The application of bicyclic guanidine for different reactions. Scheme 1.10 The application of bicyclic guanidine 50 for different reactions. Scheme 1.11 Chiral guanidine 57 catalyzed nitro Michael reaction. Scheme 1.12 Terada’s axially chiral guanidine catalyzed enantioselective reactions. Scheme 1.13 Guanidine salt catalyzed phase transfer asymmetric epoxidation of chalcones. Scheme 1.14 Guanidine salt catalyzed phase transfer asymmetric alkylation. Scheme 1.15 Guanidine salt catalyzed enantioselective Phospha-Mannich reactions. Scheme 1.16 Conjugate additions of pyrrolidine to lactones 79 catalyzed by various guanidine salts (relative rate increases are indicated). Scheme 1.17 Enantioselective Claisen rearrangement reactions catalyzed by guanidinium salt 82. Scheme 1.18 Guanidine–thiourea 85 catalyzed Henry reaction. Scheme 1.19 Bifunctional guanidine 92 catalyzed 1,4-addition reaction. Scheme 2.1 Palladium-catalyzed asymmetric synthesis of allene 98 from bromodiene 95 and nucleophile 96. Scheme 2.2 Rhodium-catalyzed asymmetric 1,6-addition of aryltitanates to enynones giving chiral allenylalkenyl silyl ethers. Scheme 2.3 Dynamic kinetic asymmetric allylic alkylations of allenes. Scheme 2.4 Olefination of ketenes with diazoacetate catalyzed by Fe(TCP)Cl. Scheme 2.5 Catalytic synthesis of allenes via isomerization of alkynes under phase transfer catalyzed conditions. Scheme 2.6 Standard synthesis of 3-alkynoates. Scheme 2.7 Preparation of tert-butyl 2-diazoacetate 120. Scheme 2.8 Synthesis of C2-symmetrical chiral bicyclic guanidines. Scheme 2.9 Chiral bicyclic guanidine 1b catalyzed isomerization of 3-alkynoate 121a in different conditions. Scheme 2.10 Enantioselective isomerization of 4-aryl 3-alkynoates 121a-h. Scheme 2.11 Asymmetric synthesis of 5-functionalized allenoates 122i-m. Scheme 2.12 Synthesis of sulfonyl alkyne 134 and its application in the enantioselective isomerization reaction. Scheme 2.13 Synthesis of propargylic ketones 138 and 141a-b. Scheme 2.14 Proposed catalytic cycle in the chiral bicyclic guanidine catalyzed isomerization of 3-alkynoates. Scheme 2.15 Proposed pre-transition-state assemblies for the chiral bicyclic guanidine catalyzed isomerization of 3-alkynoate 121a. Scheme 2.16 Preparation of functionalized chiral β-halobutenolides from chiral allenoates. Scheme 2.17 Preparation of functionalized chiral β-bromobutenolides 145d for determination of absolute configuration. 3,000 062008 #238 m AU LDS10126 UV_VIS_1 WVL:210 nm 2,500 2,000 1,500 - 12.587 - 15.147 1,000 500 -100 0.0 3,500 m in 2.5 5.0 7.5 062008 #244 [m odified by TCH LAB] m AU 10.0 12.5 15.0 LDS10135 17.5 20.0 UV_VIS_1 WVL:210 nm 3,000 2,500 2,000 - 12.9 53 1,500 1,000 500 - 16.013 -30 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 m in 20.0 178 3,000 062008 #239 [m odified by TCH LAB] m AU LDS10133 UV_VIS_1 WVL:210 nm 2,500 2,000 1,500 - 11.140 1,000 - 4.847 500 -100 0.0 3,500 m in 2.5 5.0 7.5 062008 #245 [m odified by TCH LAB] m AU 10.0 12.5 15.0 LDS10136 17.5 20.0 UV_VIS_1 WVL:210 nm 3,000 2,500 2,000 - 12.1 80 1,500 1,000 500 - 16.720 -30 0.0 m in 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 179 550 030608 #173 [m odified by TCH LAB] m AU LHJ5214A-S UV_VIS_1 WVL:210 nm - 16.920 - 18.047 400 300 200 100 -50 0.0 550 m in 5.0 10.0 030608 #174 [m odified by TCH LAB] m AU 15.0 20.0 LHJ5214A 25.0 UV_VIS_1 WVL:210 nm - 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4.113 200 150 100 50 - 37.713 -50 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 48.0 183 1,000 030608 #185 [m odified by TCH LAB] m AU LHJ52219-S UV_VIS_1 WVL:210 nm 800 600 400 - 28.267 200 -50 0.0 1,000 m in 5.0 10.0 030608 #183 [m odified by TCH LAB] m AU 15.0 20.0 25.0 LHJ5222B 30.0 34.0 UV_VIS_1 WVL:210 nm 800 600 - 15.260 - 16.307 400 200 -50 0.0 2,000 m in 5.0 10.0 030608 #184 [m odified by TCH LAB] m AU 1,500 15.0 20.0 25.0 LHJ52219 30.0 34.0 UV_VIS_1 WVL:210 nm - 15.0 80 1,000 500 - 16.360 -200 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 34.0 184 1,000 062008 #255 [m odified by TCH LAB] m AU LDS10138(2) UV_VIS_1 WVL:210 nm 800 600 400 - 29.467 - 36.047 200 -30 0.0 750 m in 5.0 10.0 15.0 062008 #262 [m odified by TCH LAB] m AU 20.0 25.0 30.0 35.0 LDS10148 40.0 45.0 UV_VIS_1 WVL:210 nm 600 500 400 300 - 31.660 200 100 - 8.893 -30 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 185 2,000 062008 #272 [m odified by TCH LAB] m AU LDS10155 UV_VIS_1 WVL:210 nm 1,500 1,000 - 22.760 - 26.980 500 -100 0.0 1,500 m in 5.0 10.0 062008 #275 [m odified by TCH LAB] m AU 15.0 20.0 25.0 30.0 LDS10157 35.0 UV_VIS_1 WVL:210 nm 1,250 1,000 750 - 25.813 500 250 - 21.920 -100 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 35.0 186 1,000 062008 #258 [m odified by TCH LAB] m AU LDS10144 UV_VIS_1 WVL:210 nm 800 600 400 - .0 87 - 4.7 200 -100 0.0 1,000 m in 5.0 10.0 062008 #251 [m odified by TCH LAB] m AU 15.0 20.0 LDS10140 25.0 UV_VIS_1 WVL:210 nm 800 600 400 - .6 67 200 - 9.5 - 3.33 87 - 5.1 0 -100 0.0 4,500 m in 5.0 10.0 062008 #279 [m odified by TCH LAB] m AU 15.0 20.0 LDS10159 25.0 UV_VIS_1 WVL:210 nm 3,000 - .6 00 2,000 1,000 - 0.2 - 4.4 - 8.4 -100 0.0 5.0 10.0 15.0 20.0 m in 25.0 187 500 030608 #179 [m odified by TCH LAB] m AU LHJ5221A-S UV_VIS_1 WVL:210 nm 400 300 - 15.4 00 200 - 21.1 73 - 12.753 - 14.0 07 100 -50 0.0 500 m in 5.0 10.0 030608 #178 [m odified by TCH LAB] m AU 15.0 20.0 25.0 LHJ5221A 30.0 UV_VIS_1 WVL:210 nm 400 300 - 15.393 200 100 - 12.740 - 21.1 93 - 14.0 07 -50 0.0 m in 5.0 10.0 15.0 20.0 25.0 30.0 188 700 030608 #162 [m odified by TCH LAB] m AU LHJ5209A1 UV_VIS_1 WVL:210 nm - 11.700 - 3.160 500 375 250 125 -100 0.0 700 m in 2.0 4.0 6.0 030608 #180 [m odified by TCH LAB] m AU 8.0 10.0 12.0 14.0 LHJ5221B1 17.0 UV_VIS_1 WVL:210 nm - 1.413 500 375 250 125 - 12.8 40 -100 0.0 m in 2.0 4.0 6.0 8.0 10.0 12.0 14.0 17.0 189 2,000 030608 #163 [m odified by TCH LAB] m AU LHJ5209A2 UV_VIS_1 WVL:210 nm - 13.5 33 1,500 - 17.033 1,000 500 -200 0.0 2,000 m in 2.5 5.0 7.5 030608 #186 [m odified by TCH LAB] m AU 10.0 12.5 15.0 17.5 LHJ5219B2 22.0 UV_VIS_1 WVL:210 nm 1,500 1,000 - 13.293 500 - 16.667 -100 0.0 m in 2.5 5.0 7.5 10.0 12.5 15.0 17.5 22.0 190 1,000 030608 #189 [m odified by TCH LAB] m AU LHJ5223 UV_VIS_1 WVL:210 nm 800 - 10.167 600 400 - 16.820 - 8.367 - 12.893 200 -100 0.0 3,000 m in 2.5 5.0 7.5 10.0 030608 #192 [m odified by TCH LAB] m AU 12.5 15.0 17.5 LHJ5226 22.0 UV_VIS_1 WVL:210 nm 2,500 - 9.993 2,000 1,500 - .240 1,000 500 - 12.607 -500 0.0 - 16.467 m in 2.5 5.0 7.5 10.0 12.5 15.0 17.5 22.0 191 Publications Hongjun Liu; Wei Feng; Yujun Zhao; Yuanhang Pan and Choon-Hong Tan.* “Organic dye-sensitized α-oxyamination irradiated by visible light.” Manuscript prepared for Green Chem Hongjun Liu; Dasheng Leow; Wei-Tian Loh and Choon-Hong Tan.* “Brønsted-base catalyzed tandem isomerisation-oxy-Michael reactions of alkynes: a novel method for synthesis of 2-alkylidenetetrahydrofurans.” Submitted for Chem. Commun Yuanhang Pan; Yujun Zhao; Ting Ma; Yuanyong Yang; Hongjun Liu; Zhiyong Jiang* and Choon-Hong Tan.* “Enantioselective synthesis of α-fluorinated β-amino acid derivatives via asymmetric Mannich reaction and selective decarboxylation reactions.” Chem. Eur. J. DOI: 10.1002/chem.200902830. Xiao Fu; Wei-Tian Loh; Yan Zhang; Tao Chen; Ting Ma; Hongjun, Liu; Jianmin Wang and Choon-Hong Tan.* “Chiral guanidinium salt catalyzed enantioselective phospha-Mannich reactions.” Angew. Chem. Int. Ed. 2009, 48, 7387–7390. Hongjun Liu; Dasheng Leow; Kuo-Wei Huang* and Choon-Hong Tan.* “Enantioselective synthesis of chiral allenoates by guanidine-catalyzed isomerization of 3-alkynoates.” J. Am. Chem. Soc. 2009, 131, 7212–7213. (Highlight by Synfacts 2009, 7, 0794–0794.) Zhiyong Jiang; Yuanyong Yang; Yuanhang Pan; Yujun, Zhao; Hongjun, Liu and Choon-Hong Tan.* “Synthesis of α-stereogenic amides and ketones via enatioselective conjugate addition of 1,4-dicarbonyl but-2-enes.” Chem. Eur. J. 2009, 15, 4925–4930. Hongjun Liu; Yuanhang, Pan; Choon-Hong Tan.* “NaNO2-catalyzed cyclization of alkenes and alkynes using molecular oxygen.” Tetrahedron Lett. 2008, 49, 4424–4426. Hongjun Liu and Choon-Hong Tan.* “Iodobenzene catalyzed iodolactonisation using sodium perborate monohydrate as the end oxidant.” Tetrahedron Lett. 2007, 48, 8220–8222. 192 Conference presentations 1. Oral presentation, Singapore International Chemistry Conference (SICC6) 2. Asian Youth Energy Summit 2008, Singapore (Dec 2009) (Apr 2008) 3. Poster presentation, 235th American Chemical Society National Meeting & Exposition, New Orleans, Louisiana, USA (Apr 2008) 4. Poster presentation, 3rd Mathematics and Physical Sciences Graduate Congress 2007 (3rd MPSGC), Kuala Lumpur, Malaysia (Dec 2007) 5. Poster presentation, Singapore International Chemistry Conference (SICC5) & APCE Asia-Pacific International Symposium on Microscale Seperation and Analysis, Singapore (Dec 2007) 193 [...]... Mannich -isomerization reaction between imine 193a and itaconimide 194a Scheme 4.3 Bicyclic guanidine 1b catalyzed enantioselective tandem Mannich -isomerization reaction between imine 193a and itaconimide 194a Scheme 4.4 Enantioselective tandem Mannich -isomerization reaction between itaconimide 194a and different imines Scheme 4.5 Synthesis of Boc type imines 193f-g Scheme 4.6 Bicyclic guanidine catalyzed. .. oxazolidinone 178 and imide 179 Scheme 3.16 Bicyclic guanidine catalyzed isomerization- aza-Michael reaction Scheme 3.17 Preparation of 3-alkynoates 187 and 189 with carbon nucleophiles Scheme 3.18 Attempts on other type of tandem isomerization- Michael reaction Scheme 3.17 Bicyclic guanidine catalyzed isomerization- aza-Michael reaction Scheme 4.1 Discovery of tandem Mannich -isomerization reaction between imine... synthesis using chiral guanidine catalysts.4 Neutral chiral guanidines are also widely used as strong bases in enantioselective reactions. 5 Chiral guanidine catalysts are generally classified into five categories: acyclic guanidines with chiral side chains, mono-to-polycyclic guanidines, axial chiral guanidines, guanidium salts, and bifunctional guanidine catalysts 1.1 Acyclic Guanidines with Chiral... Chains Scheme 1.1 Henry reaction catalyzed by homochiral guanidine Nájera group reported one of the earliest chiral guanidine catalyzed enantioselective reactions on Henry reactions in 1994.6 The best enantioselectivity was achieved with C2-symmetrical guanidine 4, affording 7a in 54% ee and 7b in 33% ee (Scheme 1.1, eq 1) Ma et al studied the diastereoselective Henry reactions of N,N-dibenzyl α-amino... enantioselectivities.24 Scheme 1.10 The application of bicyclic guanidine 50 for different reactions Scheme 1.11 Chiral guanidine 57 catalyzed nitro Michael reaction Ishikawa applied another C2-symmetrical bicyclic guanidine 50a in the TMS cyanation of aliphatic aldehydes and ketones, affording the products 52 in moderate ees (Scheme 1.10, eq 1).25 Ishikawa’s modified bicyclic guanidine 50b was used as the asymmetric... obtained in 30% ee.4 Davis also developed another bicyclic guanidine 39 to catalyze the nitro Michael reaction between 58 and 59, giving products 60 in 9-12% ee (Scheme 1.11).27 1.3 Axial chiral guanidines Scheme 1.12 Terada’s axially chiral guanidine catalyzed enantioselective reactions The chiral guanidine catalysts discussed above are either acyclic guanidine with chiral side chains or mono-to-polycyclic... CO2Bn 27a 65% yield, 43% ee 27b 82% yield, 40% ee Scheme 1.4 Ishikawa’s chiral guanidine catalyzed Michael reaction of glycinate Scheme 1.5 Enantioselective Mannich reactions of various N-Boc protected imines catalyzed by guanidine ent-22a By using monocyclic guanidine ent-22a as a catalyst, Kobayashi et al reported the Mannich reactions to give α,β-diamino esters 30 from N-Boc protected imines 28 with... guanidine catalyzed Mannich -isomerization reaction between N-Boc imine 193f and itaconimide 194a in different conditions Scheme 4.7 Enantioselective tandem Mannich -isomerization reaction between N-Eoc imine 193h and itaconimides 194 Scheme 4.8 Enantioselective tandem Mannich -isomerization reaction between N-Eoc imines 199 and itaconimide 194d Scheme 4.9 Enantioselective tandem Mannich -isomerization reaction... further research showed that guanidine 38 was not the active catalytic species involved at high temperature 1.2.2 Bicyclic guanidines In 1999, Corey and Grogan initially designed the C2-symmetric bicyclic guanidine 1c and applied it to catalytic asymmetric Strecker reaction (Scheme 1.9).18a Moderate to good ee values were achieved Subsequently, Berg et al reported that the bicyclic guanidine 1c was able to... 81-96% ee, up to >20:1dr R4 R2 R3 83 NH2 Ph N N H N H CF3 N B Ph 4 CF3 82 Scheme 1.17 Enantioselective Claisen rearrangement reactions catalyzed by guanidinium salt 82 1.5 Bifunctional guanidine catalysts Nagasawa and co-workers designed a bifunctional C2-symmetric guanidine thiourea catalyst 85 and applied to Henry reactions (Scheme 1.17).34 The bifunctional catalyst 85 effectively activated both the . BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ISOMERIZATION REACTIONS LIU HONGJUN NATIONAL UNIVERSITY OF SINGAPORE 2010 BICYCLIC GUANIDINE CATALYZED. BICYCLIC GUANIDINE CATALYZED LIU HONGJUN 2010 ENANTIOSELECTIVE ISOMERIZATION REACTIONS BICYCLIC GUANIDINE CATALYZED ENANTIOSELECTIVE ISOMERIZATION REACTIONS LIU HONGJUN (BSc., Nankai. Brønsted-base Catalyzed Tandem Isomerization- Michael Reactions 74 Chapter 4 Bicyclic Guanidine Catalyzed Asymmetric Tandem Mannich -Isomerization Reactions 4.1 Discovery of Tandem Mannich-Isomerization