Carbocycles from Carbohydrates via Free Radical Cyclizations: Synthesis and Manipulation of Annulated Furanoses

Abstract

IntroductionThe synthesis of enantiomerically pure molecules is one of the main tasks in modern synthetic chemistry. 1 Mild and simple methodologies associated with readily available starting materials are desired. In this context, sugars as raw materials 2 and free radical technologies as a method for carbon-carbon bond formation 3 are now well established choices for organic chemists. The advantages and the success of these techniques have been particularly evident in the preparation of enantiomerically pure and densely functionalized carbocycles from carbohydrates. 4My group has been working to develop new stereoselective vias for the synthesis of polyfunctionalized carbocycles from readily available carbohydrates. Particular emphasis has been devoted to the use of free radical based technologies. Moreover, we have assumed that intramolecular ring closures are well suited to the rapid assembling of chiral and complex radical precursors. Two strategies have been devised to achieve these goals: a) monosaccharide protection, opening, functionalization positioning the radical donor and the radical acceptor, and finally radical cyclization (Scheme 1, via A); b) the sugar is protected and manipulated to introduce branched chains containing the radical donor and the radical acceptor, with the anomeric position "locked" in an O-glycosylated form. In this approach an annulated sugar results around the sugar template (in pyranose or furanose form) (Scheme 1, via B). In this account we report a summary of results obtained by using the second protocol. Treatment of the radical precursor with tributyltin hydride and AIBN as promotor, at appropriate concentration and addition rate, in toluene as solvent, are the usual experimental conditions. Free radical methodology allows the conservation of the stereochemical integrity at the different stereocenters in the radical precursor. This is an important point in enantiomerically pure polyhydroxylated compounds as sugars. Another critical aspect is the potential high degree of the extent of the qualitative and quantitative asymmetric induction when new stereocenters are formed during ring closure. In this project we have learned how to modulate sugars in order to provide a wide variety of radical precursors and how to obtain efficient yields, with high diastereoselection, of the resulting carbocycles.Scheme 1 BackgroundAt the outset of this project, a plethora of reports concerning the synthesis of annulated pyranoses was available in the literature, and will not be described here in detail. The reader is referred to the exhaustive Abstract: Tributyltin hydride plus AIBN mediated free radical cyclization of chiral precursors derived from O-glycosylated carbohydrates is an efficient method for the asymmetric synthesis of carbocycles (cyclitols, aminocyclitols and pseudosugars) of biological and pharmacological interest. Starting from simple aldoses and after a series of trivial synthetic steps for hydroxyl protection and functionalization, it is possible to prepare the required ra...

Radicals in Carbohydrate Chemistry

“…A similar strategy led to the cyclohexane 117 by cleavage of the [2.2.2] bicyclic system 118. Non-template radical cyclizations in which both the radical donor and acceptor are attached to a sugar unit by pendant carbon chains provides a powerful strategy for synthesis of fused carbocycles [75]. The key step in Fraser-Reid's [76] preparation of Collum's intermediate 119 for the synthesis of phyllanthocin was achieved by Bu3SnH-promoted cyclization of the iodoaldehyde 120.…”

Macrolactamas bioativas e síntese de macrociclos por reação de carbociclização radicalar mediada por hidreto de tri-n-butilestanho

“…52,53 As principais características das reações com Bu 3 SnH, responsáveis pela sua ampla aplicação, são a relativa simplicidade do ponto de vista operacional; a ciclização ocorre sem alteração da configuração dos estereocentros de precursores quirais; a maioria dos grupos funcionais é inerte ao reagente. 54,55 No entanto, há inconvenientes: toxicidade, dificuldade em eliminar os resíduos de estanho dos produtos obtidos e formação de produtos acíclicos reduzidos. [56][57][58] Os mecanismos envolvidos nas reações com Bu 3 SnH em presença de um iniciador radicalar encontram-se bem discutidos [59][60][61][62][63][64] e estão representados para o 7-iodo-2-hepteno no Esquema 17.…”

Síntese de aliloxi-orto-iodobenzamida derivada de d-glicose e reação de ciclização radicalar mediada por hidreto de tri-n-butilestanho

“…As sínte-ses de compostos cíclicos enantiomericamente puros e altamente funcionalizados por reação de carbociclização radicalar 4 demonstram o sucesso dessa metodologia. Na reação de ciclização radicalar há conservação da integridade estereoquímica de todos os estereocentros do precursor do radical, o que é importante para manutenção da pureza enantiomérica de compostos com vários centros quirais, como os açúcares 5 . Em nossos estudos de reações de carbociclização radicalar mediadas por Bu 3 SnH visando à síntese de heterociclos [6][7][8][9][10][11][12] , mais especialmente de benzomacrolactamas e benzomacrolactonas quirais, temos usado como precursores orto-iodobenzamidas e ortoiodobenzoatos derivados de carboidratos contendo um grupo aliloxila como substituinte no anel piranosídico [6][7][8]11 .…”