Tandem isomerization reaction of alkyne total synthesis of alpha yohimbine

TANDEM ISOMERIZATION REACTION OF ALKYNES: TOTAL SYNTHESIS OF ALPHA-YOHIMBINE FENGWEI NATIONAL UNIVERSITY OF SINGAPORE 2012 TANDEM ISOMERIZATION REACTION OF ALKYNES: TOTAL SYNTHESIS OF ALPHA-YOHIMBINE FENGWEI 2012 TANDEM ISOMERIZATION REACTIONS OF ALKYNES: TOTAL SYNTHESIS OF ALPHA-YOHIMBINE FENG WEI (BSc., Nankai University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE To my family 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 would like to thank all my labmates for creating such a harmonious, encouraging, and helpful working environment. My special thanks go to Mr. Liu Hongjun for his pioneering work on the isomerization project. I thank Dr Wu Jien, Mdm Han Yanhui 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 Introduction to allenes 1.1 General introduction to allenes--------------------------------------------------------- 1.2 Intramolecular conjugate addition to allenes----------------------------------------- 1.3 Intramolecular Diels-Alder reaction of allenes-------------------------------------- 11 1.4 Summary--------------------------------------------------------------------------------- 22 Chapter Brønsted-base catalyzed tandem isomerization-aza-Michael reactions 2.1 Different approaches for the preparation of piperidines and lactams ----------- 28 2.2 Tandem isomerisation-aza-Michael reaction of alkynylamines and alkynylamides--------------------------------------------------------------------------- 35 2.3 Summary--------------------------------------------------------------------------------- 45 Chapter Total synthesis of alpha- yohimbine via intramolecular-Diels-Alder reaction 3.1 Introduction to the synthesis of alpha-yohimbine---------------------------------- 48 3.2 Tandem- isomerization intramolecular-Diels-Alder reactions of alkynoates: total synthesis of alpha-yohimbine -------------------------------------------------------- 54 3.3 Summary--------------------------------------------------------------------------------- 71 Chapter Experimental 4.1 General information-------------------------------------------------------------------- 74 4.2 Preparation and characterization of compounds for the Michael reaction ----- 75 4.3 Preparation and characterization of compounds for the IMDA reaction-------- 83 4.4 Procedures to (+)-alpha- yohimbine and characterization of compounds----- 100 Appendix-------------------------------------------------------------------------------------- 116 Summary The aim of this study is to apply the highly enantioselective alkyne isomerization reactions that is developed in our group to construct complex and usefull molucules towards natural product synthesis. We have found that a Brønsted-base catalyzed tandem isomerization-aza-Michael reaction can be used to form useful heterocycles under mild conditions. This efficient method was applied to the synthesis of various functionalized heterocycles with excellent yields. Tandem isomerization-aza-Michael reaction with alkynyl-amines, alkynyl-amide led to interesting piperidines and lactams. Asymmetric version of tandem isomerization-aza-Michael reaction using alkynyl-amide was tested to give high ee using a chiral bicyclic guanidine as a catalyst. Effort to synthesize larger ring sized lactams was carried out although failed. We have also found that chiral bicyclic guanidine could catalyze a tandem isomerisation intramolecular-Diels-Alder (IMDA) reaction. Interesting and useful hydroisoquinolines were obtained with moderate to high ees. The chirality was generated at the stage of alkyne isomerisation and transferred efficiently at the [4+2] cyclization step. We have also successfully finished the first catalytic enantioselective synthesis of alpha-yohimbine starting from the IMDA products. List of Schemes Scheme 1.1.1 Natural products containing allene structure Scheme 1.1.2 Two addition models of allenes Scheme 1.2.1 Intramolecular Michael addition of alcohol to allene sulphoxide Scheme 1.2.3 Cyclic vinyl sulfoxide and sulfone formation via intramolecular Michael addition of alcohol to allenic sulphoxide and allenic sulfone Intramolecular oxa-Michael reaction of allenyl phosphonates Scheme 1.2.4 Intramolecular Michael addition to allenotes Scheme 1.2.5 Intramolecular Michael addition to allenic ketones, example1 Scheme 1.2.6 Intramolecular Michael addition to allenic ketones, example Scheme 1.2.7 Intramolecular Michael addition to allenic ketones, example Scheme 1.2.8 Intramolecular conjugate addition of nitrogen to allenes Scheme 1.2.2 Intromolecular Diels-Alder reaction between allenic ketone and Scheme 1.3.1 furan toward the synthesis of Periplanone B Scheme 1.3.2 Intramolecular Diels-Alder reaction between allene and bezene Scheme 1.3.3 Intramolecular Diels-Alder reaction of allenic amide, example Scheme 1.3.4 Intramolecular Diels-Alder reaction of allenic amide, example Scheme 1.3.5 Intramolecular Diels-Alder reaction of sulfonyl allene Total synthesis of hippadine via intramolecular Diels-Alder reaction Scheme 1.3.6 of allenic carbonate Scheme 1.3.7 Intramolecular Diels-Alder reaction of allenyl ether Scheme 1.3.8 Euryfuran synthesis via IMDAreaction of alkoxyallene Scheme 1.3.9 Total synthesis of Forskoin via intramolecular Diels-Alder reaction of allenyl ether Scheme 1.3.10 Total synthesis of tirkentrins via Hetero-Diels-Alder reaction of allene Scheme 1.3.11 Proposal of the Intramolecular Diels-Alder reaction of vinylallene toward the total synthesis of esperamicin A Scheme 1.3.12 IMDA reaction of vinylallene toward the total synthesis of cis-Dehydrofukinone Scheme 1.3.13 IMDA reaction of vinylallene toward the total synthesis of (+)-Compactin Scheme 2.1.1 Piperidine formation via amine-ketone condensation Scheme 2.1.2 Piperidine formation via ring closing metathesis Piperidine formation via intramolecular electrophilic addition of Scheme 2.1.3 amine to allene Scheme 2.1.4 Piperidine formation via ruthenium catalysis Scheme 2.1.5 Piperidine formation via radical cyclization Scheme 2.1.6 Pyrrolidine formation via oxidative cyclization Scheme 2.1.7 Pyrrolidine formation via cobalt mediated cyclization 208da(7176B) 1,500 T emplate #132 [modified by T CH] fdw7176B mAU UV_VIS_1 WVL:210 nm 1,250 1,000 - 11.360 750 500 250 - 12.973 -100 0.0 No. 10.0 Ret.Time 20.0 Peak Name 30.0 40.0 Height Area Rel.Area mAU mAU*min % 11.36 n.a. 829.910 483.929 88.77 12.97 n.a. 101.669 61.198 11.23 931.579 545.128 100.00 Total: 50.0 208db(7176B) fdw7176B 1,500 T emplate #132 [modified by T CH] mAU UV_VIS_1 WVL:210 nm 1,250 1,000 750 500 - 36.447 250 - 27.833 -100 0.0 178 10.0 20.0 30.0 40.0 50.0 No. Ret.Time Peak Name Height Area Rel.Area mAU mAU*min % 27.83 n.a. 63.142 57.022 11.42 36.45 n.a. 305.894 442.345 88.58 369.036 499.367 100.00 Total: (7204A) IA+IA 2010230 300 T emplate #142 [modified by T CH] fdw7204A mAU UV_VIS_1 WVL:230 nm 250 200 - 22.573 - 26.140 150 100 - 23.767 - 29.953 50 -30 0.0 No. 5.0 Ret.Time 10.0 15.0 Peak Name 20.0 25.0 30.0 35.0 Height Area Rel.Area mAU mAU*min % 22.57 n.a. 187.129 98.149 35.73 23.77 n.a. 64.880 40.789 14.85 26.14 n.a. 161.353 98.817 35.98 29.95 n.a. 48.909 36.911 13.44 462.271 274.666 100.00 Total: 40.0 179 208fa (7209) 2,000 T emplate #151 [modified by T CH] fdw7209 mAU UV_VIS_3 WVL:210 nm 1,500 - 22.907 1,000 500 - 26.560 -30 0.0 No. 5.0 10.0 Ret.Time 15.0 Peak Name 20.0 25.0 30.0 35.0 Height Area Rel.Area mAU mAU*min % 22.91 n.a. 955.640 652.162 82.54 26.56 n.a. 180.696 137.934 17.46 1136.336 790.096 100.00 Total: 40.0 208fb (7209) fdw7204C 1,500 T emplate #139 [modified by T CH] mAU UV_VIS_2 WVL:254 nm 1,250 1,000 750 500 250 - 29.807 - 23.707 -100 0.0 180 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 No. Ret.Time Peak Name Height Area Rel.Area mAU mAU*min % 23.71 n.a. 15.291 6.643 10.55 29.81 n.a. 76.987 56.344 89.45 92.278 62.988 100.00 Total: (7217) AD+AD 2010230 fdw7217 300 T emplate #145 [modified by T CH] mAU UV_VIS_1 WVL:230 nm - 26.453 250 - 32.307 200 150 100 - 35.107 50 -20 0.0 No. - 46.893 10.0 Ret.Time 20.0 30.0 Peak Name 40.0 50.0 60.0 Height Area Rel.Area mAU mAU*min % 26.45 n.a. 253.946 269.899 36.68 32.31 n.a. 236.165 267.775 36.40 35.11 n.a. 80.771 101.649 13.82 46.89 n.a. 39.806 96.409 13.10 610.688 735.732 100.00 Total: 70.0 181 208ga(7218) 800 T emplate #146 [modified by T CH] fdw7218 mAU UV_VIS_1 WVL:230 nm 625 - 32.080 500 375 250 125 - 26.407 -20 0.0 No. 10.0 Ret.Time 20.0 30.0 Peak Name 40.0 50.0 60.0 Height Area Rel.Area mAU mAU*min % 26.41 n.a. 113.000 109.982 15.90 32.08 n.a. 520.009 581.562 84.10 633.009 691.544 100.00 Total: 70.0 208gb(7218) 600 T emplate #146 [modified by T CH] fdw7218 mAU UV_VIS_1 WVL:230 nm 500 400 300 200 100 - 34.753 -50 0.0 182 - 46.533 10.0 20.0 30.0 40.0 50.0 60.0 70.0 No. Ret.Time Peak Name Height Area Rel.Area mAU mAU*min % 34.75 n.a. 2.873 1.965 5.10 46.53 n.a. 18.460 36.539 94.90 21.332 38.504 100.00 Total: (10257B racemic) IA0505210 1,200 T emplate #258 [modified by fdw10257B T CH] racemic mAU UV_VIS_1 WVL:210 nm 1,000 - 11.353 800 - 12.827 600 400 200 - 19.587 - 30.213 -150 0.0 No. 5.0 Ret.Time 10.0 15.0 Peak Name 20.0 25.0 30.0 Height Area Rel.Area mAU mAU*min % 11.35 n.a. 820.119 442.261 41.73 12.83 n.a. 730.318 453.532 42.80 19.59 n.a. 95.021 82.064 7.74 30.21 n.a. 53.037 81.877 7.73 1698.496 1059.734 100.00 Total: 35.0 183 208ha(Fdw10257B) 1,000 T emplate #257 [modified by Tfdw10257B CH] mAU UV_VIS_1 WVL:210 nm 800 - 11.413 600 400 200 - 12.900 -150 0.0 No. 5.0 Ret.Time 10.0 15.0 Peak Name 20.0 25.0 30.0 Height Area Rel.Area mAU mAU*min % 11.41 n.a. 572.142 318.666 93.36 12.90 n.a. 42.654 22.660 6.64 614.796 341.327 100.00 Total: 35.0 208hb(Fdw10257B) fdw10257B 800 T emplate #257 [modified by T CH] mAU UV_VIS_1 WVL:210 nm 625 500 375 250 125 - 30.173 - 19.673 -150 0.0 184 5.0 10.0 15.0 20.0 25.0 30.0 35.0 No. Ret.Time Peak Name Height Area Rel.Area mAU mAU*min % 19.67 n.a. 6.486 5.440 5.94 30.17 n.a. 42.169 86.146 94.06 48.656 91.586 100.00 Total: (6153A IC 2010210) fdw6153A 150 T emplate #77 [modified by T CH] mAU UV_VIS_3 WVL:210 nm 125 100 - 28.367 75 - 39.233 50 - 20.627 25 - 50.380 -20 0.0 No. 10.0 Ret.Time 20.0 30.0 Peak Name 40.0 50.0 60.0 Height Area Rel.Area mAU mAU*min % 20.63 n.a. 39.832 31.684 14.49 28.37 n.a. 72.730 78.051 35.70 39.23 n.a. 52.440 77.598 35.49 50.38 n.a. 16.231 31.316 14.32 181.232 218.649 100.00 Total: 70.0 185 208ia(6157B) 500 T emplate #82 [modified by T CH] fdw6157B mAU UV_VIS_3 WVL:210 nm 400 - 36.867 300 200 100 - 27.027 -20 0.0 No. 10.0 20.0 Ret.Time 30.0 Peak Name 40.0 50.0 60.0 Height Area Rel.Area mAU mAU*min % 27.03 n.a. 31.929 31.876 6.51 36.87 n.a. 314.382 457.704 93.49 346.311 489.580 100.00 Total: 70.0 208ib(6157B) 500 T emplate #82 [modified by T CH] fdw6157B mAU UV_VIS_3 WVL:210 nm 400 300 200 100 - 47.100 - 19.920 -20 0.0 186 10.0 20.0 30.0 40.0 50.0 60.0 70.0 No. Ret.Time Peak Name Height Area Rel.Area mAU mAU*min % 19.92 n.a. 10.687 6.298 4.50 47.10 n.a. 73.856 133.622 95.50 84.543 139.920 100.00 Total: 208haa IC1010230 (fdw10208.2) racemic 50.0 T emplate #198 mAU fdw10208.2 UV_VIS_1 WVL:230 nm - 14.000 40.0 - 18.060 30.0 20.0 10.0 0.0 -10.0 -20.0 0.0 No. 5.0 Ret.Time 10.0 Peak Name 15.0 20.0 25.0 Height Area Rel.Area mAU mAU*min % 14.00 n.a. 39.723 33.897 50.06 18.06 n.a. 31.631 33.813 49.94 71.354 67.710 100.00 Total: 30.0 187 (11029.2) chiral 300 T emplate #261 [modified by T CH] fdw11029.2 mAU 250 - 14.633 UV_VIS_1 WVL:230 nm 200 150 100 50 - 19.820 -50 0.0 No. 5.0 Ret.Time 10.0 15.0 Peak Name 20.0 25.0 Height Area Rel.Area mAU mAU*min % 14.63 n.a. 248.287 253.329 91.68 19.82 n.a. 17.897 22.985 8.32 266.184 276.315 100.00 Total: 30.0 208hbb IC 1010230 (fdw10208.1) racemic 300 T emplate #199 mAU fdw10208.1 UV_VIS_3 WVL:254 nm 200 - 13.167 - 24.540 100 -100 0.0 188 5.0 10.0 15.0 20.0 25.0 30.0 35.0 No. Ret.Time Peak Name Height Area Rel.Area mAU mAU*min % 13.17 n.a. 175.800 135.423 49.98 24.54 n.a. 101.102 135.516 50.02 276.902 270.939 100.00 Total: fdw11029.1 chiral 1,500 T emplate #260 [modified by Tfdw11029.1 CH] mAU UV_VIS_1 WVL:230 nm - 13.773 1,200 1,000 800 600 400 200 - 27.327 -50 0.0 No. 5.0 Ret.Time 10.0 15.0 Peak Name 20.0 25.0 30.0 Height Area Rel.Area mAU mAU*min % 13.77 n.a. 1185.044 1142.111 89.44 27.33 n.a. 80.712 134.839 10.56 1265.756 1276.951 100.00 Total: 35.0 189 221 (fdw10131) 80 IC 1010254 racemic T emplate #204 [modified by T CH] fdw10131 mAU UV_VIS_1 WVL:254 nm 60 40 - 13.173 - 17.687 20 -20 0.0 5.0 No. Ret.Time 10.0 Peak Name 15.0 20.0 25.0 Height Area Rel.Area mAU mAU*min % 13.17 n.a. 36.508 28.741 49.53 17.69 n.a. 29.468 29.285 50.47 65.976 58.026 100.00 Total: 30.0 fdw10215 chiral 1,000 T emplate #206 [modified by T CH] fdw10215 mAU UV_VIS_1 WVL:254 nm 800 - 13.047 600 400 200 - 17.527 -100 0.0 190 5.0 10.0 15.0 20.0 25.0 30.0 No. Ret.Time Peak Name Height Area Rel.Area mAU mAU*min % 13.05 n.a. 673.317 635.175 87.81 17.53 n.a. 78.342 88.182 12.19 751.659 723.356 100.00 Total: 222 (fdw10130) IC1010254 racemic fdw10130 100 T emplate #209 [modified by T CH] mAU UV_VIS_1 WVL:254 nm 80 60 - 14.360 40 - 21.027 20 -30 0.0 No. 5.0 Ret.Time 10.0 Peak Name 15.0 20.0 25.0 Height Area Rel.Area mAU mAU*min % 14.36 n.a. 47.588 33.203 48.58 21.03 n.a. 32.812 35.144 51.42 80.400 68.347 100.00 Total: 30.0 191 fdw10217 chiral 100 T emplate #210 [modified by T CH] fdw10217 mAU UV_VIS_1 WVL:254 nm 80 - 21.013 60 40 20 - 14.393 -30 0.0 No. 5.0 Ret.Time 10.0 Peak Name 15.0 20.0 25.0 Height Area Rel.Area mAU mAU*min % 14.39 n.a. 10.294 7.729 10.56 21.01 n.a. 58.427 65.490 89.44 68.721 73.219 100.00 Total: 30.0 227 (FDW10207) AD1010(30mins)->1030230 racemic fdw10207 200 T emplate #220 [modified by T CH] mAU UV_VIS_2 WVL:230 nm 150 - 40.853 - 37.933 100 50 -20 30.0 192 35.0 40.0 45.0 50.0 55.0 60.0 No. Ret.Time Peak Name Height Area Rel.Area mAU mAU*min % 37.93 n.a. 114.622 117.133 51.08 40.85 n.a. 119.569 112.200 48.92 234.191 229.334 100.00 Total: FDW10220.2 chiral fdw10220.2 500 T emplate #221 [modified by T CH] mAU UV_VIS_1 WVL:254 nm 400 - 40.233 300 200 100 - 37.773 -20 30.0 No. 35.0 Ret.Time 40.0 Peak Name 45.0 50.0 55.0 Height Area Rel.Area mAU mAU*min % 37.77 n.a. 19.135 16.124 7.33 40.23 n.a. 344.631 203.987 92.67 60.0 193 [...]... Scheme 2.2.4 Synthesis of the chiral bicyclic guanidine 149 Scheme 2.2.5 Synthesis of alkynyl amide 150 Scheme 2.2.6 Synthetic schemes to different alkynyl amides and carbonates Scheme 2.2.7 Enantioselective isomerization of alkynes to allenes Scheme 3.1.1 Total synthesis of alpha- yohimbine, route1 Scheme 3.1.2 Total synthesis of alpha- yohimbine, route 2 Scheme 3.1.3 Total synthesis of alpha- yohimbine, ... 3.2.10 Total synthesis of alpha- yohimbine starting from 208ha and 208hb List of Tables Table 1.3.1 Table 2.1 Intramolecular [4+2] cycloaddition of allenic acid and ester Solvent effect on asymmetric tandem isomerization- aza-Michael reaction of alkynyl amine 141c Table 2.2 Bicyclic guanidine catalyzed enantioselective tandem isomerization- aza-Michael reaction Table 3.1 Solvent effect on IMDA reaction. .. 3 Scheme 3.1.4 Total synthesis of alpha- yohimbine, route 4 Scheme 3.2.1 Initial plan for the construction of hydroisoquinoline derivative, core sutructure of yohimbines Scheme 3.2.2 Synthesis of IMDA substrates containing opening diene Scheme 3.2.3 Synthesis of IMDA substrates containing cyclic diene Scheme 3.2.4 X-ray structures of the compounds 208ba, 208ca and the X-ray structure of the hydrogenation... hydrogenation product of compound 208bb Scheme 3.2.5 Intramolecular-Diels-Alder reaction of substrate 208g and manipulation on the IMDA product 208ga Scheme 3.2.6 Attempt on the total synthesis starting with compound 208ca Scheme 3.2.7 Ring opening of compound 217 with triflic acid Scheme 3.2.8 Protection of alcohol group in compound 221 Scheme 3.2.9 Total synthesis of alpha- yohimbine 170 starting... 2.1.8 β–lactam synthesis via [2+2]-cycloaddition Scheme 2.1.9 5-membered lactam formation via gold catalysis Scheme 2.1.10 6-membered lactam formation via aza-oxy-carbanion relay Scheme 2.2.1 Alkynyl amine synthesis Brø nsted-base Scheme 2.2.2 catalyzed tandem isomerization- aza-Michael reaction of alkynyl-amines 141 Proposed mechanism for tandem isomerization- aza-Michael Scheme 2.2.3 reaction of 141 Scheme... reaction Table 3.2 Solvent and concentration effect on the IMDA reaction of 208b Table 3.3 Intramolecular-Diels-Alder (IMDA) reaction of 208 Table 3.4 Oxabicyclic ring opening of IMDA product 208ca Table 3.5 Optimization of reductive oxabicyclic ring opening of IMDA product 208ca Table 3.6 Optimization of hydrogenation of compound 222 List of Figures Figure 1.1 Allene models Figure 2.1 Piperidine or pyridine... opening of the oxybridge in 77 to give the furan transfer product 78 Repeating this process via the intermediate 79 led to the final target euryfuran 80 Scheme 1.3.8 Euryfuran synthesis via IMDA reaction of alkoxyallene An asymmetric synthesis of the intermediate 84 of forskolin by Nagashima in 1990 also employed intramolecular Diels-Alder reaction of allenyl ether (Scheme 1.3.9).35 Treatment of propargyl... have been performed on the synthesis and study of intramolecular cyclization of phosphorylated allenic carbinols In 2001, Brel reported an intramolecular oxa-Michael reaction of allenyl phosphonates (Scheme 1.2.3).11 The glycols 21a–i were easily prepared from Scheme 1.2.3 Intramolecular oxa-Michael reaction of allenyl phosphonates propargylic alcohols and obtained as a mixture of two diastereomers (31... conjugate addition of amine to allene.22 When the chiral allene 44 was treated with AgNO 3 , the piperidine 45 was obtained in good yield and the natural product (R)-(-)-Coniine was achieved in two more steps The axial chirality of allene was fully transferred to the central chirality of the product 1.3 Intramolecular Diels-Alder reactions of allenes Hydrogenation of one carbon-carbon double bond of allene... number of atoms that each component contributes to the ring construction Among these cycloaddition reactions, the [4+2] Diels-Alder reaction is the most important and useful in natural product synthesis 23 Because it leads to increasing molecular complexity, especially for intramolecular cyclization As a result, the intramolecular Diels-Alder reaction of allene (either as dienophile or part of diene) . TANDEM ISOMERIZATION REACTION OF ALKYNES: TOTAL SYNTHESIS OF ALPHA-YOHIMBINE FENGWEI 2012 TANDEM ISOMERIZATION REACTIONS OF ALKYNES: TOTAL SYNTHESIS OF ALPHA-YOHIMBINE FENG. Enantioselective isomerization of alkynes to allenes Scheme 3.1.1 Total synthesis of alpha-yohimbine, route1 Scheme 3.1.2 Total synthesis of alpha-yohimbine, route 2 Scheme 3.1.3 Total synthesis of alpha-yohimbine, . TANDEM ISOMERIZATION REACTION OF ALKYNES: TOTAL SYNTHESIS OF ALPHA-YOHIMBINE FENGWEI NATIONAL UNIVERSITY OF SINGAPORE 2012 TANDEM ISOMERIZATION REACTION