Jon Tangaa Jensen Studies towards the total synthesis of latrunculin A and latrunculin B Acknowledgements A thank to Prof. Dr. A. Fürstner for accepting me in his group and for his kind interest in my project. I would also like to thank Dr. Liliana Parra-Rapado for her preliminary work on the project and for her suggestions for the work on latrunculin B. Likewise, I would like to thank Dr. Dominic DeSouza for his important contribution to the latrunculin B project and for finishing the total synthesis of latrunculin B. Also a thank to Karin Radkowski for constantly being helpful with anything practical in the lab. Furthermore I would like to thank Dr. Martin Albert for fruitful discussions and interesting suggestions to my project. Also I would like to thank Dr. Frank Glorius, Gereon Altenhoff, Kristian Burstein, Andrea Jantsch, Fabian Feyen, Dr. Jacques Ragot, Andreas Leitner and Dschun Song for a good working atmosphere on the 6th floor, and Doris Kremzow and Stefan Prühs for a friendly atmosphere in general. The other members of the Fürstner group just like previous members of the Fürstner group are thanked for their help, support and interest in my work. Furthermore, the technical staff and the administration at the MPI in Mülheim are thanked for their friendly help. i Contents General theory 1 Latrunculines 5 Previous syntheses of latrunculin 9 Latrunculines by metathesis 12 Previous work in the group 16 Studies towards latrunculin B and A 21 Ketone fragment 21 The aldehyde fragment 26 The aldol reaction 32 Latrunculin A 36 Preparation of the molybdenum precatalyst 44 Ring closing enyne-yne metathesis 49 Aldol reaction for latrunculin A 51 Alkene cross metathesis 55 Vinyl ketone synthesis 60 Conclusion 64 Experimental 69 General information 69 Analytical methods 69 Chemicals prepared in the group 71 Experimental procedures 71 Literature 104 Appendix 1 111 ii Abbreviations Ac Acetyl acac Acetylacetonate aq. Aqueous Bn Benzyl br Broadened CM Cross Metathesis conc. Concentrated Cy Cyclohexyl d Doublet δ Chemical Shift dba Dibenzylidene Acetone DMAP N, N’-Dimethylaminopyridin DMF Dimethylformamid DMPU N, N’-Dimethylpropyleneurea DMSO Dimethylsulfoxide EA Ethyl Acetate e.e. Enantiomeric Excess EI Electron Ionisation eq Equivalent Et Ethyl Fig. Figure GC-MS Gas Chromatography-Mass Spectrometry HPLC High-Performance Liquid Chromatrography Hz Hertz IR Infra Red J Coupling Constant KHMDS Potassium Hexamethyldisilazane LAH Lithium Aluminium Hydride LDA Lithium Diisopropyl Amide m Multiplet MCPBA m-Peroxybenzoic acid Me Methyl Mes Mesitylene MHz MegaHertz min Minutes m/z Mass/Charge MTBE Methyl tert-Butyl Ether n Normal n -BuLi Lithium n-Butylide NaHMDS Sodium Hexamethyldisilazane NMO N-Methylmorpholine-N-oxide NMR Nuclear Magnetic Resonance Ph Phenyl PMB p-Methoxybenyl Py Pyridine q Quartet RCAM Ring Closing Alkyne Metathesis Red-Al Sodium bis(2-Methoxyethoxy)aluminium Hydride iii r.t. Room Temperature s Singlet SEM (Trimethylsilyl)ethoxymethyl t Triplet TBAF Tetrabutylammonium Fluoride TBDMS tert-Butyldimethylsilyl tert Tertiary Teoc 2-(Trimethylsilyl)ethyl Carbamoyl Tf Triflate THF Tetrahydrofurane TLC Thin Layer Chromatography TMS Trimethylsilyl TPAP Tetra-n-propylammonium Perruthenate UV Ultra Violet iv General theory In recent years metathesis reactions have become increasingly important because of the development of a number of catalysts that are efficient and tolerant to a variety of functional groups, allowing olefin and alkyne metathesis to be used as key step in total synthesis.1 The metathesis itself is a formal exchange of alkylidene or alkylidyne moieties of a pair of alkenes or alkynes (Fig. 1). R1 R2 R1 R2 + + R' R' 1 2 R' R' 1 2 Fig.1: General reaction scheme for metathesis. Olefin metathesis was first reported in a patent in 19552 and became industrially important in the following decades.3 The first catalysts were typically chlorides or oxychlorides of tungsten, molybdenum or rhenium catalyzed by cocatalysts such as trialkyl aluminium or diethyl aluminium chloride. However, the oxophilicity of these compounds and the operational temperatures of more than 100 °C limited the scope of the reaction. The industrially important catalysts were mostly heterogeneous, but homogeneous catalysts were also employed.4 Alkene metathesis became synthetically relevant after Schrock et al. reported the homogeneous catalyst 1 which is able to perform alkene metathesis at ambient temperature.5 In the following years Grubbs published two other homogeneous catalysts, 26 and 3,7 that are in some cases also active at ambient temperature and tolerate even the presence of water (Fig. 2). PCy3 PCy3 N Cl Cl F C Ru Ph Ru 3 Mo Cl Cl Ph F3C O Ph PCy Ph PCy O 3 3 F3C CF3 23 1 Fig. 2: Homogeneous catalysts for alkene metathesis. 1 The accepted mechanism of alkene metathesis was proposed by Chauvin. It involves two four membered metallacycles and two metal carbenes.8 The metal carbene A adds to an alkene via a formal [2+2] cycloaddition to give the metallacycle B, which reacts via a [2+2] cycloreversion to give ethene and a new metal carbene, C. The latter then adds to another alkene to give metallacycle D which undergoes a [2+2] cycloreversion that results in a new product and regenerates the catalytically active metal carbene A (Fig. 3). R1 R1 R2 MCH2 A R R 1 M M 1 D B H C CH2 2 R2 C R1 M H2CCH2 R2 Fig. 3: The Chauvin mechanism for alkene metathesis. In 1974 the first catalytic system for alkyne metathesis was published by Mortreux et al. who reported that a 1:6 mixture of hexacarbonyl molybdenum and resorcinol is catalytically active.9 However, the reaction temperature of 160 °C constitutes a serious disadvantage. Although the catalytic system was further improved by changing to phenol and adjusting the ratio of hexacarbonyl molybdenum the phenol, a reaction temperature of 140 °C is still required, limiting the method to alkynes with no acid- or heat sensitive functionalities.10 In 1982 Villemin et al. reported that alkynes with ester-, acetate-, bromide- or carboxylic acid groups undergo alkyne metathesis when treated with hexacarbonyl molybdenum and p-chloro phenol in refluxing octane, whereas alkynes containing nitriles or alcohols only gave low conversions.11 In 1995 Mori et al. used the Mortreux catalyst to perform alkyne cross metathesis, showing that unsymmetrical alkynes could be obtained in good yields by this route.12 The catalytic system of Mortreux was further improved by Bunz et al. by 2 changing the solvent to o-dichlorobenzene, using p-(trifluoromethyl)phenol as additive and purging the reaction with nitrogen.13 In 1995 Mori proposed a reaction mechanism for alkyne metathesis without being able to prove the mechanism experimentally (Fig. 4).14 R R R R R R R R R R Mo Mo R' R' R' R' R' Mo R' R' R' Mo Mo R' R' Fig. 4: The mechanism proposed by Mori for alkyne metathesis with the Mortreux catalyst. In 1975 Katz suggested a possible reaction mechanism for alkyne metathesis, the alkylidyne mechanism, involving two metallacycylobutadienes as intermediates (Fig. 5).15 This mechanism was verified experimentally by Schrock in the case of a tungsten-based catalyst.16 R R' R R' R R' R' R ++ M M M M R' R' R' R' Fig. 5: The alkylidyne mechanism for alkyne metathesis. A much more reactive and structurally well defined catalyst for alkyne metathesis was discovered by Schrock in 1981 (Fig. 6).17 The tungsten (VI) complex 4 is catalytically active at ambient temperature, thus broadening the scope of alkyne metathesis significantly. For example, in 1998 Fürstner et al. reported the first ring closing alkyne metathesis with this catalyst and showed that it was possible to prepare 12 to 28 membered rings with ester or amide functionalities in good yields.18 The importance of this result followed from the fact that alkynes can be selectively reduced to Z-configured alkenes, and thus macrocyclic alkenes with a defined configuration of the double bond became accessible by a metathesis route. The tungsten-alkylidyne catalyst 4 developed by Schrock and co-workers17 is sensitive towards donor groups such as thioethers, polyethers or amines. It does, however, tolerate the presence of free amide protons. 3 In 1999 Fürstner et al. published another catalyst for alkyne metathesis and ring closing alkyne metathesis based on the molybdenum complex 5 (Fig. 6).19 O N Mo N O W N O 4 5 Fig. 6: The Schrock catalyst and the Cummins complex used by Fürstner et al. as precatalyst. The molybdenum-based precatalyst 5 was originally reported by Cummins in 1995.20 The complex per se is inactive, but when treated with chlorinated solvents such as dichloromethane at ambient temperature, two different well defined complexes arise, both of which are active catalysts for alkyne metathesis. H Cl N Mo CH Cl N Mo N Mo N 2 2 N N N r.t. N + N 5 67 Fig. 7: Initial activation of 5 by CH2Cl2 reported by Fürstner et al. This catalytic system is in some aspects complementary to the Schrock catalyst 4 since it is less sensitive to donor ligands that deactivate the latter. Therefore it can be applied to substrates containing thioethers, basic tertiary nitrogen atoms or polyether chains.19 However, catalysts 6 and 7 do not tolerate unprotected alcohols or free amide protons. In 2003 Moore et al. extended the method developed by Fürstner and published a similar catalyst 8.21 The modification made by Moore on this catalytic system gave a catalyst that performs well in presence of unprotected amides (Fig. 8).21 4 Cl N Mo N CHCl N Mo 2 N Mo N N r.t. N N + N 5 Mg 6 8 Fig. 8. The modification of the Fürstner catalyst developed by Moore et al.