Titanium(IV) enolate chemistry applied to the stereoselective construction of C–C and C–O bonds. New ionic and radical processes

In the present Thesis we continued a previous study of the nucleophilic character of titanium(IV) enolates. Particularly,we focused our attention on the analysis of substrate-controlled Michael additions to enones and other acceptors.Thus, the Michael addition of (S)-2-benzyloxy-3-pentanoneto enones was thoroughly evaluatedin Chapter 1. In the case of vinyl ketones, the best reaction conditions involved the use of two TiCl4 equivalents and afforded the 2,4-antiadducts as single diastereomers in excellent yields. In addition, the developed methodology was also evaluated with β- substituted enones, whose optimised conditions using TiCl4 and SnCl4 afforded the 2,4- anti-4,5-antiadducts with diastereoselectivities above 90:10 in all cases with good yields. Furthermore, the Michael addition of (S)-2-benzyloxy-3-pentanoneto α,β- unsaturated nitroalkenes was alsoanalysed inChapter 1. The use of two equivalents of TiCl4and aromatic nitroalkenes led to the 2,4-anti-4,5-syn adducts with excellent yields and diastereoselectivities. In turn, aliphatic nitroalkenes needed optimised conditions using TiCl4 and SnCl4 to afford the 2,4-anti-4,5-syn adducts in good diastereoselectivities and yields. Finally, the nitro group was converted into other useful functional groups. Another objective of the first part of this thesis wasto re-evaluate the synthesis of the tetrahydropyran ring from the C1-C9 fragment of herboxidiene/GEX1A. Thus, in Chapter 2 we analysed the initial retrosynthesis of the C1-C9 fragment and studied the oxa-Michael cyclization. Finally, we designed two parallel sequences to improve the first synthetic approach.The stereoselective synthesis of the tetrahydropyran ring was successfully accomplished following two different approaches. In approach 1, the number of steps was increased, but the sequence pursued a fully stereoselective pathway taking advantage of the great selectivity offered by a dimethylpyrrole amide under acidic conditions attaining a 54% yield (46% for the original approach). In approach 2, the original sequence of reactions was followed, but the suppression of unnecessary purification operations and a final isomerisation step increased notably the yield up to 58% (39% for the original approach). Keepingin mind the biradical character of certain titanium enolates, the second objective of this Thesis was to examine the uncommon radical reactivity of titanium enolates derived from chiral N-acyl oxazolidinones when exposed to radical reagents. In Chapter 3, the aminoxylation of chiral N-acyl oxazolidinones was improved using a chiral tert-butyl oxazolidinethionederived from tert-leucine. This chiral auxiliary provided the aminoxylated products as single diastereomers in all cases with excellent yields. Finally, the resulting adducts were transformed into synthetical useful intermediates. Furthermore, in Chapter 3 we also reported a highly stereoselective oxidation of titanium enolates from chiral N-acyl oxazolidinones with molecular oxygen. The direct hydroxylation of biradical titanium(IV) enolates derived from chiral oxazolidinones with O2 proved to be feasible. Thus, we described a novel approach for the synthesis of enantiomerically pure α-hydroxy carboxylic derivatives. We describe in Chapter 4 a comprehensive search of compounds capable of participating in radical reactions, which involved a brief exploration of photoredox catalysis. Finally, such research led to the discovery of a new and highly stereoselective alkylation with aliphatic diacyl peroxides. Decarboxylation of the diacyl peroxides from aliphatic acids promoted by the titanium enolates produced primary and secondary radicals and triggered the formation of the alkylated adducts as single diastereomers with excellent yields.En la presente Tesis continuamos un estudio previo sobre el carácter nucleófilo de los enolatos de titanio(IV) en adiciones de Michael con control por sustrato. Así, la adición de Michael de (S)-2-benciloxi-3-pentanona a enonas y nitroalquenos se evaluó a fondo en el Capítulo 1. En el caso de las vinil cetonas, las mejores condiciones de reacción implicaban el uso de dos equivalentes de TiCl4 o un equivalente de TiCl4 y otro de SnCl4 y proporcionaban los aductos 2,4-anti-4,5-anti con rendimientos excelentes y diastereoselectividades superiores a 90:10. Además, la metodología desarrollada también se empleó con nitroalquenos α,β-insaturados, conduciendo a proporcionar los aductos de 2,4-anti-4,5-syn con buenas diastereoselectividades y rendimientos. En el Capítulo 2 se reevaluó la retrosíntesis inicial del anillo tetrahidropiránico del fragmento C1-C9 del herboxidieno/GEX1A. La síntesis estereoselectiva del anillo de tetrahidropirano se logró con éxito siguiendo dos enfoques diferentes. En el primer enfoque, se aumentó el número de pasos, pero la secuencia siguió una ruta completamente estereoselectiva aprovechando la gran selectividad ofrecida por una dimetilpirrolamida en condiciones ácidas. En el segundo enfoque, se siguió la secuencia original, pero la supresión de operaciones de purificación innecesarias y la inclusión de una etapa de isomerización final aumentaron notablemente el rendimiento. El segundo objetivo de esta Tesis fue examinar la reactividad radical poco común de enolatos de titanio derivados de N-acil oxazolidinonas quirales cuando se exponen a reactivos radicalarios. Así, en el Capítulo 3, la aminoxilación de N-acil oxazolidinonas quirales se mejoró usando una tiazolidintiona de tert-butilo quiral derivada de tert-leucina que proporcionó los productos aminoxilados como únicos diastereómeros con rendimientos excelentes. Además, en el Capítulo 3 también llevamos a cabo una hidroxilación directa altamente estereoselectiva de enolatos de titanio a partir de N-acil oxazolidinonas quirales con oxígeno para la síntesis de derivados α-hidroxicarboxílicos enantioméricamente puros. En el Capítulo 4 describimos una búsqueda exhaustiva de compuestos capaces de participar en reacciones radicales, lo que implicó una breve exploración de la catálisis fotoredox. Finalmente, tal investigación llevó al descubrimiento de una nueva alquilación altamente estereoselectiva con peróxidos de diacilo alifáticos que conducía a la formación de los aductos alquilados como diastereómeros únicos con rendimientos excelentes