A Regio- and Stereodivergent Route to All Isomers of vic-Amino Alcohols Berit Olofsson Doctoral thesis Stockholm, 2002 Royal Institute of Technology Department of Chemistry Organic Chemistry Akademisk avhandling som med tillstånd av Kungl Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av teknologie doktorsexamen i kemi fredagen den 25:e oktober kl 13.00 i Kollegiesalen, KTH, Valhallavägen 79, Stockholm. Avhandlingen försvaras på engelska. Opponent är Prof. K. J. Hale, University College London. ISBN 91-7283-353-X ISRN KTH/IOK/FR--02/72--SE ISSN 1100-7974 TRITA-IOK Forskningsrapport 2002:72 © Berit Olofsson, 2002 Ekonomi-Print AB, Stockholm Abstract The first part of this thesis describes a synthetic strategy that provides all eight possible isomers of a given vic-amino alcohol starting from vinylepoxides. The value of a general route is evident, as several isomers are needed in investiga- tions of structure-activity relationships for pharmacologically active derivatives, and for optimizing the performance of chiral ligands containing the amino alco- hol moiety. Vinylepoxides, obtained in high enantiomeric excess, were ring-opened both with inversion and retention of stereochemistry, delivering two diastereomeric amino alcohols with high regio- and stereoselectivity. Via ring-closure to aziridi- nes and subsequent regioselective ring-opening with suitable oxygen nucleo- philes, the two remaining amino alcohols were selectively achieved. Within this study, two efficient protocols for the regioselective and stereo- specific aminolysis of vinylepoxides have been presented. Compared to previous methods, these procedures use milder reaction conditions, shorter reaction times, generally give higher yields and are applicable to a larger set of substrates. Fur- thermore, the ring-closure of vic-amino alcohols to the corresponding N-H viny- laziridines has been investigated. Three routes have been found useful, which one is preferred depends on substrate and scale. In the second part of the thesis, the synthetic strategy is applied on the synthe- sis of Sphingosine and its regio- and stereoisomers. Moreover, a rapid way of determining relative configuration of vic-amino alcohols is described, which should be of substantial use when amino alcohols are formed by diastereoselec- tive reactions. Berit Olofsson; A Regio- and Stereodivergent Route to All Isomers of vic- Amino Alcohols. Department of Chemistry, Organic Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden. Keywords: amino alcohols, vinylepoxides, vinylaziridines, oxazolines, oxa- zolidinones, ring-opening, regioselective, diastereoselective, sphingosine, con- figuration, NMR spectroscopy. Table of contents Abstract Abbreviations List of publications Chapter 1 Introduction 1 1.1 Vicinal amino alcohols 2 1.2 Synthesis of amino alcohols 3 1.3 Aim of the study 8 1.4 Synthetic strategy 8 Chapter 2 Synthesis of Vinylepoxides 1 IV 11 2.1 Introduction 11 2.2 Synthesis of vinylepoxides 1 13 Chapter 3 Aminolysis of Vinylepoxides 1 to anti-Amino Alcohols 2 I-IV 17 3.1 Conventional Aminolysis 17 3.2 Microwave-assisted aminolysis 18 3.3 Large Scale Aminolysis 19 Chapter 4 Pd(0)-catalyzed Epoxide Opening leading to syn-Amino Alcohols 3 II-IV 23 4.1 Pd(0)-catalyzed Ring-Opening of 1 23 4.2 Detosylation and Hydrolysis 25 Chapter 5 Ring-closure of anti-Amino Alcohols 2 to Vinylaziridines 4 II-V 27 5.1 Background to aziridines 27 5.2 Investigation of ring-closure strategies 28 5.3 Synthesis of vinylaziridines 4b-f 32 Chapter 6 Solvolysis of Vinylaziridines 4 to anti-Amino Alcohols 5 II-IV 35 6.1 Introduction 35 6.2 Solvolysis of vinylaziridines 4 36 Chapter 7 Aziridine Rearrangement leading to syn-Amino Alcohols 6 II-IV 39 7.1 Acetylation 40 7.2 Rearrangement 40 7.3 Hydrolysis 42 Chapter 8 Synthesis of Sphingosine and its Regio- and Stereoisomers VI 45 8.1 Background 45 8.2 Synthesis of vinylepoxide 1l 46 8.3 Ring-openings of vinylepoxide 1l 49 8.4 Synthesis and ring-openings of vinylaziridine 4l 50 Chapter 9 Determination of Regiochemistry and Relative Stereochemistry of vic-Amino Alcohols IV, VII 53 9.1 Introduction 53 9.2 Synthesis of Oxazolidinones 54 9.3 NMR determination 56 Concluding remarks 59 Acknowledgments 60 Appendices 61 Papers I –VII Abbreviations ∆ heat BINOL 1,1-bi-2-naphtol Boc t-butoxy carbonyl Cbz benzyloxycarbonyl dba dibenzylideneacetone DEAD diethyl azodicarboxylate DET diethyl tartrate (DHQ) PHAL hydroquinine 1,4-phtalazinediyl diether 2 DIAD diisopropyl azodicarboxylate DIBALH diisobutylaluminum hydride DMAP 4-dimethylaminopyridine dr diastereomeric ratio ds diastereoselectivity es enantioselectivity HRMS high resolution mass spectroscopy IBX 2-iodoxybenzoic acid Ipc isopinocampheyl KHMDS potassium hexamethyldisilazane LDA litium diisopropylamide mCPBA m-chloroperbenzoic acid NMI 1-methylimidazole Ms methanesulfonyl NOE nuclear Overhauser effect PMB p-methoxybenzyl SAE Sharpless asymmetric epoxidation TBHP t-butyl hydroperoxide TFA trifluoroacetic acid TMS trimethylsilyl TPAP tetrapropylammonium perruthenate Tr trityl = triphenylmethyl Ts p-toluenesulfonyl vic vicinal List of publications This thesis is based on the following publications, in the text referred to by their Roman numerals I-VII. I. Microwave-assisted Aminolysis of Vinylepoxides Berit Olofsson, Ulf M. Lindström and Peter Somfai Tetrahedron Lett. 1999, 40, 9273-9276. II. A Regio- and Stereodivergent Synthesis of vic-Amino Alcohols Berit Olofsson, Uttam Khamrai and Peter Somfai Org. Lett. 2000, 2, 4087-4089. III. A Regio- and Stereodivergent Route to All Isomers of vic-Amino Alcohols, Berit Olofsson and Peter Somfai Latvijas J. Chem. 2002, 1, 69-78. IV. A Regio- and Stereodivergent Route to All Isomers of vic-Amino Alcohols, Berit Olofsson and Peter Somfai J. Org. Chem. in press. V. Synthesis of N-H Vinylaziridines: A Comparative Study Berit Olofsson, Roel Wijtmans and Peter Somfai Tetrahedron 2002, 58, 5979-5982. VI. Divergent Synthesis of D-erythro-Sphingosine, L-threo-Sphingosine and their Regioisomers Berit Olofsson and Peter Somfai Manuscript. VII. Determination of the Relative Configuration of vic-Amino Alcohols Berit Olofsson and Peter Somfai Submitted. Introduction 1 One of the main objectives of organic chemistry has always been the synthesis of natural products, as they can often be isolated from Nature only in minor amounts. Very complex molecules have been synthesized as early as in the 1950s, albeit in poor total yields. In the last decades chemists have, besides synthesizing extraordinarily complicated compounds, focused on optimizing already present reactions and developing new reactions which could simplify and shorten these syntheses. Great efforts to develop libraries of efficient reactions for each type of transformation have been made, in order to simplify the design of complex molecules. With these libraries at hand, each subunit of a complex molecule can be synthesized by means of well-known techniques, presupposed that the subunits can be combined in a later stage. Many natural products contain one or more stereogenic centers, which complicate their syntheses substantially. Asymmetric synthesis is one of the most expanding fields in organic chemistry, since the discovery that the two enantiomers of a chiral compound can have different pharmacological effect. This can be exemplified by propranolol, which was introduced in the 1960s for the treatment of heart disease. The (-)-enantiomer is a potent β-blocker, whereas the (+)-enantiomer acts a contraceptive (Figure 1).1 N O O N H H OH OH (-)-Propranolol (mirror plane) (+)-Propranolol Figure 1: The two enantiomers of propranolol. Asymmetric reactions are often developed from well-known procedures. Chiral auxiliaries or catalysts bearing chiral ligands can be utilized to afford induction towards one of the possible isomers. As the research on new 1 Aitken, R. A.; Kilényi, S. N. Asymmetric synthesis; Blackie Academic & Professional: Glasgow, 1992. 1 asymmetric processes is continuously increasing, the need for novel chiral auxiliaries and ligands is extensive.2,3 1.1 Vicinal amino alcohols The β-amino alcohol moiety is found in a wide variety of biologically active alkaloids and peptides.4 The subunit is also present in many synthetic, pharmacologically active molecules. Hydroxyamino acids constitute a major group among the naturally occurring amino alcohols. Lipids and lipid-like molecules often contain an amino alcohol moiety, as exemplified by sphingosine (Figure 2). This compound is the major backbone in glycosphingolipids, which are vital in cell recognition events such as growth, differentiation and immune response. Cyclic amino alcohols constitute a third group, where the amino residue is contained within a ring. Representatives of this group are deoxynojirimycin, which is an α-glycosidase inhibitor with therapeutic potential due to its low cytotoxicity, and quinine that is used as a drug for the treatment of malaria, high fever and other diseases.4 OH OH O HOH H HO OH HO (CH2)12Me OH N H NH N 2 H N Sphingosine Deoxynojirimycin Quinine Figure 2: Examples of natural products incorporating a vic-amino alcohol moiety. Peptidomimetics are the most common among synthetic, pharmacologically active compounds containing a vic-amino alcohol subunit. This group of peptide analogues is typified by the HIV protease inhibitor saquinavir (Figure 3).4 Ph O R1 O HN N O S NH O O O H N N O OH N Ph R R' R R Saquinavir Oxazolidinone Bis(oxazoline) Figure 3: Vic-amino alcohol derivatives used in asymmetric synthesis. The importance of vicinal amino alcohols is also well recognized in asymmetric synthesis, as many chiral auxiliaries and ligands contain this substructure. Some representative examples of amino alcohol-derived compounds are shown in Figure 3. Evans’ oxazolidinones are utilized as chiral auxiliaries in various reactions, e.g. asymmetric alkylations. Bisoxazolines are employed as ligands in enantioselective cyclopropanations and aziridinations.2,3 2 Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-875. 3 Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Wiley: New York, 1995. 4 Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576. 2