A synthetic approach to palmerolides via Negishi cross coupling. The challenge of the C15-C16 bond formation

The esterification of fragment C1-C8 (2) with fragment C16-C23 (3) to give iodo derivative 4, followed by a Pd-catalysed coupling with a C9-C15 fragment (7 or 8), may provide a common precursor of most palmerolides. Ligands and reaction conditions were exhaustively examined to perform the C15-C16 bond formation via Negishi reaction. With simple models, pre-activated Pd-Xantphos and Pd-DPEphos complexes were the most efficient catalysts at RT. Zincation of the C9-C15 fragment (8) and cross coupling with 4 required 3 equiv of t-BuLi, 10 mol % of Pd-Xantphos and 60 °C

Síntesis Total de la Anfidinolida B(2)

En el transcurso de esta tesis se ha trabajado en la síntesis total de la Anfidinolida B2. Ésta es una macrolactona citotóxica aislada de un dinoflagelado marino (Amphidinium sp.) por el grupo de Shimizu y colaboradores en Brewer’s Bay, St. Thomas, Virgin Island. Como los espectros de la Anfidinolida B2 son muy parecidos al de la Anfidinolida B1 (cristalizada y cuya configuración absoluta pudo determinarse por Rayos X y experimentos de degradación), B2 se consideró un epímero en C18 de la B1. Sin embargo, su estructura sigue siendo incierta ya que Carter et al. sintetizaron la estructura propuesta por Shimizu y observaron que los datos espectroscópicos no coincidían con la natural. La retrosíntesis planteada en nuestro grupo se basa en cuatro desconexiones principales que dan lugar a cuatro fragmentos de complejidad estructural. El Fragmento I se ha sintetizado a través de una alilación asimétrica de la cetona metílica, transformación apenas usada en síntesis totales. Después de probar varias metodologías optamos por utilizar la alilación asimétrica de Schaus, que nos proporcionó nuestro alcohol alílico en un 95% de rendimiento y una relación enantiomérica de 95:5. De esta manera pudimos optimizar la síntesis de primera generación de este fragmento llevada a cabo por la Dra. Mireia Sidera, obteniendo el alcohol en 3 etapas y un rendimiento total del 32%. El Fragmento II, se ha conseguido sintetizar a través de un exhaustivo estudio de la apertura del 3,5-dimetiltetrahidrofuran-2-ol donde el 2,2,2-trifluoroetanol es un aditivo clave en la olefinación de Wittig para evitar la posible adición conjugada que da lugar al producto cíclico. La síntesis del fragmento se ha llevado a cabo a través de una dihidroxilación asimétrica de Sharpless, formación de la amida de morfolina y posterior intercambio a cetona vinílica. La síntesis del Fragmento III ha supuesto un estudio de la reacción de Negishi, donde se ha intentado realizar un coupling Csp3–Csp2, habiendo sido imposible obtener altos rendimientos. No obstante, la unión de un intermedio del Fragmento III con el Fragmento I, también mediante reacción de Negishi, nos ha permitido formar el enlace C13–C14 de la Anfidinolida B2. Una vez realizada esta unión, sí que se ha podido llevar a cabo la unión Csp3–Csp2 para alargar la cadena del Fragmento III y acabar epoxidando mediante una reacción organocatalítica de Jørgensen la posición α,β del aldehído que sirve para la unión con el Fragmento IV. Los resultados de los experimentos de la reacción de Negishi han servido para extrapolarlos a otros acoplamientos que habían resultado problemáticos con anterioridad en el grupo. Así, se ha realizado la síntesis de la Palmerolida A, macrólido inhibidor del melanoma aislado en 2006 por Baker y colaboradores, aplicando las condiciones optimizadas con anterioridad. Finalmente, la síntesis del Fragmento IV mediante reacciones triviales nos ha llevado a la unión de éste con el Fragmento Oeste a través de la reacción de Julia-Kocienski. Actualmente nos encontramos estudiando la saponificación y posterior esterificación para la obtención del macrociclo que dará lugar a la Anfidinolida B2.The present Doctoral Thesis describes our efforts towards the Total Synthesis of Amphidinolide B2, a novel macrolide with potent cytotoxicity against lymphoma murine cells and humane carcinoma cells. It is a 26-membered ring macrolactone, with an allylic epoxide, four doble bonds and 9 stereogenic centres. However, the absolute configuration is still unknown as Carter and co-worker sinthetised the proposed structure and observed that the spectroscopic data were not in agreement with those reported by Shimizu. They propose a new structure for Amphidinolide B2, where the two alcohols in C16 and C18 have a syn relative configuration. Our retrosynthesic analysis was based in four main disconnections that lead to four principal fragments. The synthesis of Fragment I has been optimized using a methyl ketone asymmetric allylation of ketones developed by Schaus. In this manner, the synthesis of the fragment could be achieved in 3 steps and 32% overall yield. Fragment II was envisage via an olefination reaction of lactol 1.9. However, this reaction was not trivial and an exhaustive study was carried out. Finally, using Wittig olefination reaction with 0.9 equivalents of ylide or 2.0 equivalents of trifluoroethanol, the product could be obtained. Negishi reaction has also been studied for the Csp3–Csp2 coupling. After several optimizations, we have been able to synthesize Western Fragment with this protocol. Finally, Jørgensen’s catalytic asymmetric epoxidation allowed us to the formation of the α,β-epoxy aldehyde. Taking advantage of the Negishi reaction study performed bellow, we decided to focus our attention in the challenging C15–C16 bond formation of Palmerolide A, a melanoma-inhibiting macrolide. After some studies changing the protecting group, we obtained the coupling product in 78% yield. Fragment IV is the simplest of all. The synthesis starts from γ-butirolactone and sulfone 6.1 is obtained in 4 steps and 53%. This compound was used for the Julia–Kocienski olefination obtaining 6.3 in moderate yield. Unfortunately, we haven’t had enough time to continue with the synthesis, which implies a saponification, sterification of Fragment II, ring-closing metathesis to form the macrolactone and the final directed oxi-Michael adition to obtain the C18 stereogenic center

Comparing and taming the reactivity of HWE and Wittig reagents with cyclic hemiacetals

A practical solution to the formation of mixtures of E/Z and open/cyclic isomers in the reaction of (2R,4S)-4-hydroxy-2-methylpentanal (as its hemiacetal, a lactol) with conjugated phosphoranes (stabilised Wittig reagents) and Horner-Wadsworth-Emmons reagents is disclosed. The HWE reaction has a strong bias to give oxolanes. On the other hand, stabilised Wittig reagents give unsaturated carboxyl derivatives of configuration E (major) and oxolanes (minor); the latter can be avoided by addition of CF3CH2OH or using morpholine amide phosphorane

A synthetic approach to palmerolides via Negishi cross coupling. The challenge of the C15-C16 bond formation

The esterification of fragment C1-C8 (2) with fragment C16-C23 (3) to give iodo derivative 4, followed by a Pd-catalysed coupling with a C9-C15 fragment (7 or 8), may provide a common precursor of most palmerolides. Ligands and reaction conditions were exhaustively examined to perform the C15-C16 bond formation via Negishi reaction. With simple models, pre-activated Pd-Xantphos and Pd-DPEphos complexes were the most efficient catalysts at RT. Zincation of the C9-C15 fragment (8) and cross coupling with 4 required 3 equiv of t-BuLi, 10 mol % of Pd-Xantphos and 60 °C