Luận án tiến sĩ: Ứng dụng phản ứng Oxa [3+3] cycloaddition - Aleksey Kurdyumov

UNIVERSITY OF MINNESOTA This is to certify that I have examined this copy of a doctoral thesis by Aleksey Valeryevich Kurdyumov and have found that it is complete and satisfactory in all respects, and that any and all revisions required by the final examining committee have been made. Hsung Signature of Facyfty AdvisoP ð$~4ƒ- 2000 Date GRADUATE SCHOOL Applications of the Formal Oxa-[3 + 3] Cycloaddition to Natural Product Synthesis A THESIS SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY Aleksey Valeryevich Kurdyumov IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Prof. Hsung, Advisor May 2006 UMI Number: 3220012 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction.

In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. ® UMI UMI Microform 3220012 Copyright 2006 by ProQuest Information and Learning Company. All rights reserved.

This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P. Box 1346 Ann Arbor, MI 48106-1346 © Aleksey Valeryevich Kurdyumov 2006 Acknowledgments First and foremost, I want to thank my wife, Yelena and both of my daughters, Yekaterina and Victoria, for their emotional support during the writing of this thesis and through my time as a graduate student. I also thank my advisor, Dr.

Hsung for his input into my development and for giving me the exiting projects. I appreciate his kindness and understanding along the way, and for putting up with me for all this time. I want to thank my undergraduate advisor, Dr. Brisbois, for taking me into his lab, as a second-year student at Hamline University and getting me interested in synthetic organic chemistry, and for allowing me to continue research in his lab at Macalester College.

I want to acknowledge my academic advisor at Hamline University, Dr. John Matachek, for bribing me with money through MacCorkle Scholarship. This changed my major from Biology to Chemistry in a flash. All members of Dr.

Richard Hsung group deserve thanks. In particular, I want to thank, Dr. Kevin Cole, Dr. Lichen Shen and Dr.

Yu Tang for being my lab partners; Aleksey Gerasyuto for help with computations and useful conversations; Nan Lin, Jacob Swidorski, Nadja Sydorenko and Glen Gullickson, for their help with one of the projects. In addition, I want to thank Dr. Victor Young for his invaluable help with obtaining crystal structure; Dr. Letitia Yao for her help with my NMR questions; Dr.

Christopher Leitheiser for teaching me how to use prep HPLC; Dr. Dana Reed for training me on HRMS. Dedicated to Yelena il Abstract 171 words Aleksey Valeryevich Kurdyumov, University of Minnesota, Minneapolis, MN 55455 Advisor: Richard P. Hsung For several years in our laboratory we have investigated the formal [3 + 3] cycloaddition.

This is a condensation reaction that occurs between an unsaturated aldehyde and a 1,3-diketone or equivalent. The reaction results in a new 2H-pyran or 2H-pyridine fused to the diketone. Chapter I of this thesis concentrates on new developments in the area of oxa-[3 + 3] cycloaddition reaction, in particular, Lewis acid catalyzed version of this reaction. Synthetic scope and limitations of this new methodology are discussed.

Chapter II describes synthetic approaches towards naturally occurring chromenes and chromanes. Our total syntheses of such compounds, rhododaurichromanic acid A and B, methyl ester of daurichromenic acid and hongoquercin A, are discussed in detail. Unusual, exo-type polyene cyclization and unique cationic [2 + 2] cycloaddition are also discussed, through divergent syntheses of rhododaurichromanic acid A and hongoquercin A. Total syntheses of daldiniapyrone, annularin B andF are described in the last chapter.

11 Table of Contents Acknowledgemenfs. --- cọ nọ như i ˆ 0y Lm. iii Table of Contents.cccscssccsscssecesccsscesccnscescescesssensenseessesoescoes iv List of AbbrevÏafÏons. co cu nu ng 0 n0 vỉ Chapter I.

Formal [3 + 3] Cycloaddition Reaction Catalyzed by Lewis AcÏds. ch nh nh kg 1 1. on HH nh nha 3 1.3 Lewis Acids and Formal [3 + 3] Cycloaddition.5 The Scope and Synthetic Value. HH HH nh nh ea ees 21 1.

HH nh kh nh sy 32 1. HH HH nh Km vê 33 1. cà cv ii 35 Chapter II. Syntheses of Chromenes and Chromanes.- nee cene eee TH SH ng KH nh nh hy vn 43 2.3 Rhododaurichromanic Acid A & B and Daurichromenic Acid.5 Previous Work: Rhododaurichromanic Acid A & B and Daurichromenic ÁGCId.

TH n nh kg 52 2.6 Previous Work: Hongoquercin A and B.7 _ Approaches to Chiral Chromanoids.8 Our Approach To Chromenes and Chromanes.9 _ Total Syntheses of Rhododaurichromanic Acids A & B and Methyl Ester of Daurichromenic Acid.10 Total Synthesis of Hongoquercin A.11 Polyene Cyclization and Cationic [2 + 2] Cycloaddition.12 Approach Toward Hongoquercin B. HS HH teen enna ene Ki kế 108 2.c se 111 Chapter III. Daldiniapyrone and Annularins. ch HH nh n nh e nena es 143 3.

ch kh kg 146 3. Results and DIisCussion. ch nh Hy 155 3.5 Overall ConcÌuSion. HH HH ene khe, 156.

ecce ccc ee eee e nent nena e eee eeneeeseneeneeneeneenenaess 157 3. Selected NMR Spectra. , 166 Chapter I NMR Spe€CfTA.cQQQ eee HH HH HH nh nh ru 167 Chapter II NMR Sp€ctra.cQQQnn HH ene eee enn eenees 170 Chapter TI NMR Spectra. ch kg 204 Appendix IT.---Q Ăn nh rap 218 Abbreviations A Angstrom(s) Ac Acetyl anhyd anhydrous APCI Atmospheric pressure chemical ionization aq Aqueous Ar Aryl Bn Benzyl BTEAC Benzyltriethylammonium chloride n-Bu normal-Butyl t-Bu tert-Butyl cat.

Catalytic calcd calculated Cy Cyclohexyl ỗ Chemical shift in ppm d day(s) dba Dibenzylidene acetone dppf bis-(Diphenylphosphino) ferrocene DBU 1,8-Diazabicyclo[4.0]undec-7-ene DCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DEAD diethyl azodicarboxylate DET diethyl tartrate DIBAL-H Diisobuty] aluminum hydride DMAP 4-Dimethylamino pyridine DMF Dimethylformamide DME 1,2-Dimethoxyethane DMP Dess-Martin periodinane, 2,2-dimethoxypropane, or 3,4-dimethoxyphenyl DMSO dimethyl sulfoxide ee enantiomeric excess vì ESI Electrospray ionization Et Ethyl EtOAc Ethyl acetate equiv Equivalent FTIR Fourier transform infrared absorption spectroscopy GC Gas chromatography hour(s) [H] Reduction HMDS bis(trimethylsilyl)amide HMPA Hexamethylphosphoric triamide hv Irradiation with light HPLC High-pressure liquid chromatography HRMS High resolution mass spectroscopy Hz Hertz Im Imidazole IR Infrared absorption spectroscopy iPr Isopropyl Spin-spin coupling constant in hertz KHMDS Potassium bis(trimethylsilyl)amide LAH Lithium aluminum hydride LCMS Liquid chromatography/mass spectroscopy LDA Lithium diisopropyl amide mCPBA m-Chloroperbenzoic acid Methyl] MEM 2-methoxyethoxymethyl MHz Megahertz mmol Millimoles mol Moles MOM Methoxymethyl mp Melting point Vil MPLC Medium pressure liquid chromatography ms Molecular sieves NaHMDS Sodium bis(trimethylsilylamide NBS N-Bromosuccinimide NCS N-Chlorosuccinimide NMO N-Methylmorpholine-N-oxide NMR Nuclear magnetic resonance spectrometry nOe Nuclear Overhauser effect Nu Nucleophile [O] Oxidation PEG Polyethylene glycol Ph Phenyl PhH Benzene PhMe Toluene pip Piperidine PM3 Parameterized Model 3 PMB 4-Methoxybenzyl ppm Parts per million PPTS Pyridinium para-toluene sulfonate p-Tol Para tolyl py Pyridine Ry Retention factor rt Room temperature sat Saturated SEM 2-(trimethylsily])ethoxymethyl TBAF Tetra-N-butylammonium fluoride TBHP tert-Butylhydroperoxide TBDPS tert-Butyldiphenylsilyl TBS tert-Butyldimethylsilyl TES Triethylsilyl Vill TESH Triethylsilane TEMPO Tetramethylpiperdinyloxy free radical TẾ Trifluoromethanesulfonate TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TIPS Triisopropylsilyl TLC Thin layer chromatography TMEDA N, N, N’, N’-tetramethylethylenediamine TMS Trimethylsilyl or tetramethyl silane TOF/MS Time of flight mass spectroscopy tol Toluene TPAP Tetra-N-propylammonium perruthenate TsOH para-Toluene sulfonic acid 1X Chapter I: Introduction and Background Chapter I Formal [3 + 3] Cycloaddition Reaction Catalyzed by Lewis Acids 1.1 Introduction Cycloaddition and annulation reactions remain a widely used method for the construction of cyclic compounds. An attractive feature, which makes these reactions a powerful synthetic tool, is their ability to conveniently build multiple bonds simultaneously with regio- and stereochemical control leading to polycyclic carbocycles and heterocycles. For several years in our laboratory we have been investigating a formal [3 + 3] cycloaddition reaction.' During this time we have demonstrated the versatility of the [3 + 3] cycloaddition reaction and also applied it to syntheses of several natural products.ˆ“ © AcO Xã Oo NR, O ae | C-1,2-addition ị | ie ⁄ X | Rị X Rạ X 'Rị Ro 2 4 X= OH or NP oo P= protecting group B-elimination O Ôn lọ) electrocyclic bề ring-closure Oo R1 x R RLt. Chapter I: Introduction and Background Mechanistically, this reaction proceeds through the sequence shown in Scheme 1.

This is a tandem process that involves a step-wise Knoevenagel-type condensation between an œ,B-unsaturated iminium salt 1 and a diketone equivalent 2. This process consists of C-1,2-addition followed by B-elimination. 6n-electron electocyclic ring- closure of 1-oxatriene 3 leads to the formation of 1-oxadecalin 4. The result of this process is the formation of two new o-bonds in addition to generation of a new stereocenter adjacent to the heteroatom.

It can be considered formally an equivalent of a [3 + 3] cycloaddition in which the three carbon atoms of œ,B—unsaturated iminium salt 1 have been added to the two carbon atoms and one oxygen atom of diketone. The term [3 + 3] cycloaddition was adapted by us from Seebach’s work describing a Stork-type carbo-[3 + 3] annulation reaction between nitroalkenes and enamines.” Two types of hetero-[3 + 3] cycloadditions have been studied in our lab and we termed them aza-[3 + 3] and oxa-[3 + 3] which produce l-azadecalin and 1-oxadecalin respectfully. These reactions can be further classified as intermolecular or intramolecular. This Chapter gives a brief history of formal [3 + 3] cycloaddition reaction by providing summary of previous work in our, as well as, other research laboratories but predominantly focuses on new developments in the area of [3 + 3] cycloaddition.

In particular, it comprehensively describes our effort to develop a new Lewis acid catalyzed method and its advantages, as well as, limitations. Detailed experimental procedure is included at the end. Selected 'H NMR spectra could be found in the Appendix. Chapter I: Introduction and Background 1.° Michael type additions were carried out by refluxing 5 and 6 in pyridine and the condensation products 7 were converted to the corresponding cyclic methyl ketals by refluxing in methanolic HCl, followed by elimination to provide 8.

This transformation required harsh conditions; in addition, the reaction required an extra elimination step to produce a [3 + 3] type product. 6) OH Q CO ` Ri pyr, reflux OH HCl R' _1) MeOH, HO Ọ PM LA Ac;O, HCIO¿ en Co R2 _AoO.HOO, oO” *O 7 Scheme 2. The next step was taken several years later by de Groot, who studied the reaction between cyclic 1,3-diketone and an œ,B-unsaturated aldehyde as illustrates in Scheme 3.’ When dicarbonyl 9 and aldehyde 10 were refluxed in dry pyridine, high yields of the cyclized product 11 resulting from 1,2 addition were obtained. The use of enals proved to be crucial for the further development; it gave the reaction a new twist and also demonstrated the potential use of the [3 + 3] cycloaddition.

It was now a one-pot reaction capable of making oxadecalins, such as 11, in moderate to high yields. Unfortunately, we struggled to repeat these results in our laboratories. An important observation was also made. The condensation product 12, resulting from an acyclic dione 13 and enal 14, 3 Chapter I: Introduction and Background existed in both closed and open form.

Compounds 12 and 15 could be separated, but both gradually equilibrated to the original mixture. pyridine ẹ _ Tefux | NN 70% 0 11 O O _feflux pyridine | Sy __ seu O O 12 15 Scheme 3. Another maJor development came from the detailed study by Moreno-Mafias in 1985.° He disclosed the reaction that involved condensation of 6-methyl-4-hydroxy-2- pyrones 16 with œ,/đunsaturated aldehyde catalyzed by piperidinium acetate leading to a variety of products 17-21 (Scheme 4). These compounds, resulting from various competing pathways, were scrupulously isolated and analyzed.