Synthesis and Application of Chiral Carbocations
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DEGREE PROJECT, INORGANIC CHEMISTRY , SECOND LEVEL STOCKHOLM, SWEDEN 2015 Synthesis and Application of Chiral Carbocations ANA ALICIA PALES GRAU KTH ROYAL INSTITUTE OF TECHNOLOGY CHE Acknowledgements I wish to acknowledge my research mentor Prof. Johan Franzén for accepting me in his group and his mentorship during the whole project. His valuable suggestions were very fruitful for the completion of the project. I would also like to thank my research group for their continuous support and valuable inputs. I am grateful to Organic Chemistry department in KTH for providing me the necessary facilities and a great laboratory environment. I must mention my gratitude to my home university Universitat Politècnica de València and my host university KTH Royal Institute of Technology and Erasmus Plus exchange programme of EU. Finally, I would like to thank my family and friends for their continuous encouragements during this whole period. 1 Abstract Asymmetric synthesis is most significant method to generate chiral compounds from prochiral substrates. It usually involves a chiral catalysis, which can be either metal based or organo-catalysis. Both of these systems have their own advantages and disadvantages. In recent times, organocatalysts are gathering widespread attention due to their low toxicity and inexpensive nature. Organocatalysts can replace traditional metal based Lewis acid catalysts in several useful organic transformations like the Diels-Alder reactions. Carbocations are compounds with positively charged carbon atoms and they can activate the substrate by pulling its electrons thus making it more electrophilic. Though carbocations are well-known in literature, they are not well explored in catalysis despite their tremendous potential. The aim of this project is to synthesize new chiral carbocations, derived from different chiral auxiliaries and substitution on aromatic moiety and to investigate them in asymmetric Diels- Alder reactions. We envisioned the final product to be enantio-enriched as the carbocations are chiral in nature. We have synthesized several chiral secondary and tertiary alcohols as a precursor of carbenium salts. These alcohols were mainly synthesized by addition of Grignard reagent or organolithium reagents to the carbonyl compounds. Though, we have synthesized several chiral alcohols, only three carbocations could be isolated those having methoxy group in the aromatic ring. The methoxy group was found to be crucial for the stabilization of the carbocation. All the isolated carbocations were able to catalyze the Diels-Alder reactions, however it was found that carbocation 4 with BF4 as a counter ion was better reactive than others. Unfortunately, we could not get any chiral induction with the use of these catalysts. We believe that with better tuning in catalysts structure and the reaction conditions these carbocations might able to produce chiral induction in the product. 2 List of Abbreviations BINOL 1,1'-Bi-2-naphthol BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene ee Enantiomeric excess TfOH Triflurometahnesulfonic acid DCM Dichloromethane Tr Trityl Cp Cyclopentyl TBS tert-Butyldimethylsilyl EWG Electron withdrawing group LUMO Lowest Unoccupied Molecular Orbital HOMO Highest Occupied Molecular Orbital LA Lewis Acid DMAP Dimethylamino pyridine TsCl para-Toluene sulfonyl chloride r.t. Room Temperature o.n. Over Night DMF Dimethyl formamide THF Tetrahydrofuran DIAD Diisopropylazodicarboxylate NMR Nuclear Magnetic Resonance * Chiral Center w.r.t. with respect to 3 Table of contents 1 Introduction…………………………………………………………………5 1.1 Chirality…………………………………………………………………5 1.2 Chiral Catalysis (Asymmetric catalysis)………………………………..5 1.3 Chiral Lewis Acid Catalysis…………………………………….............6 1.4 Different type of metal free Lewis acid catalysis……………………….7 1.4.1 Silyl cation based catalysts………………………………………..7 1.4.2 Carbocations………………………………………………………9 2 Aim of this Project…………………………………………………………15 3 Results and Discussion……………………………………………………..17 3.1 Design and synthesis of the chiral carbocation 1……………………….17 3.2 Design and attempted synthesis of the chiral carbocation 2……………19 3.3 Design and attempted synthesis of chiral carbocation 3………………..22 3.4 Design and Synthesis of chiral carbocation 4…………………………..24 3.5 Design and attepmted synthesis of carbocation 5………………………26 3.6 Design and attempted synthesis of carbocation 6………………………27 3.7 Catalytic evaluations of carbocations in Diels-Alder and hetero Diels-Alder reaction…………………………………………………….29 4 Conclusion and outlook……………………………………………………31 5 Experimental part…………………………………………………………..32 6 References…………………………………………………………………45 4 1 Introduction “The universe is dissymmetrical; for if the whole of the bodies which compose the solar system were placed before a glass moving with their individual movements, the image in the glass could not be superimposed on reality……….. Life is dominated by dissymmetrical actions. I can foresee that all living species are primordially, on their structure, in their external generates functions of cosmic dissymmetry.” -Louis Pasteur, 1848[1] 1.1 Chirality “Chirality is an all-encompassing phenomenon” (Blaser et al. 2012) which is unveiled by both macroscopic as well as microscopic objects found in nature. In molecular terms chirality, a geometrical phenomenon outcomes in the “dual existence” (termed as enantiomers) of a molecule. The two enantiomers have same chemical structure and they are non-superimposable mirror image to each other. In this context it is not surprising that the biological and therapeutic activity of a chiral substance depends upon their stereochemistry, since all highly living organisms are chiral.[2] The one enantiomer of the racemic mixture (eutomer) is biologically active whereas the other (distomer) is either fatal or inactive.[3] This is the reason behind the fact that more than one third of the marketed drugs are chiral in nature and the regulator will approve the new drugs with an asymmetric centre only in one enantiomeric form.[4] 1.2 Chiral Catalysis (Asymmetric catalysis) Prior to the tragedy caused with the use of racemic thalidomide as a sedative, came into light in early 60s, only a few synthetic methods for the preparation of chiral compounds were known. In 1970, the development of the asymmetric synthesis started and now there are numerous methods to obtain a chiral compound. These methods can be broadly categorized in three different routes, viz., (i) Resolution of the racemates to provide single enantiomers (ii) The chiral pool synthetic approach and (iii) Asymmetric synthesis. 5 However, among them asymmetric synthesis, mostly achieved by a chiral catalyst (metal catalyst or organo-catalyst), is a most general way to obtain optically pure compounds due to broad substrate scope and flexibility to synthesize any of the desired enantiomer. A catalyst provides an alternative route for the reaction with lower activation energy (Figure 1). Thus catalysts can enable a reaction which is either very slow or not progressing at all. Asymmetric catalysis on the other hand work by lowering the activation energy differently from one enantiomer to other enantiomer, which is done by asymmetric induction, involves substrate, reagent, catalyst or environment. Figure 1. Kinetic profile of a catalyzed reaction. 1.3 Chiral Lewis Acid Catalysis Lewis acids are electrophilic compounds, which mean they are capable of accepting a pair of electrons. The Lewis acidic compounds can act as a catalyst due to their ability to activate the substrates by pulling away electrons making them more electrophilic. In general Lewis acid catalysis is metal based. Main group metals such as aluminum, boron, silicon, and tin, as well as many early (titanium, zirconium) and late (iron, copper, zinc) d-block metals can attract electron from electronegative atom in the substrate, such as oxygen (both sp2 or sp3), nitrogen, sulfur, and halogens. Hence, classical carbon-carbon or carbon-heteroatom bond formation reactions such as Diels-Alder, Ene-reaction or Friedel-Crafts reaction can be catalyzed by metal based Lewis acid catalysts. The asymmetric versions of these reactions are also well explored where a chiral ligand scaffold (such as BINOL, BINAP, bis-oxazolines 6 etc.) that is coordinated to the Lewis acidic metal centers provided the necessary chiral induction. Though the term Lewis acid catalysis is mostly generalized to metal based catalysts however, organic compounds like carbenium, silyl, phosphonoum cations or hypervalent compounds based on silicon or phosphorous also exhibit Lewis acidic activity. The advantages with metal free Lewis acid catalysts are that they are simple organic molecules and thus any contamination due to metal source during the synthesis of biologically or pharmaceutically active compounds can be avoided. [5] 1.4 Different type of metal free Lewis acid catalysis In this section some selective examples of metal free Lewis acidic catalysis particularly in asymmetric synthesis have been discussed. 1.4.1 Silyl cation based catalysts Silicon based Lewis acid catalysis are of particular importance due their ability to catalyze a broad variety of reactions and also compatible with many carbon nucleophiles like silyl enol ethers, allyl organometallic reagents and cuprates. Lewis acidic silyl based catalysts can be divided in two categories based on the strength of the counter anion which is not discussed in details here. The first use of silicon based Lewis acid in asymmetric Diels-Alder reaction was reported by the groups