The development of new reaction methodologies requiring only a catalytic amount of promoter are fundamentally important to the advancement of organic synthesis. 1 Coupled with a mode for enantioinduction, these strategies become indispensable tools for the generation of optically pure molecules in a reasonably atom-economical and environmentally conscious manner. Cycloaddition reactions constitute a special class since such multiple bond forming processes create much greater molecular complexity than single bond forming reactions.The palladium-catalyzed [3+2] cycloaddition of trimethylenemethane (Pd-TMM) to electron deficient π-systems was introduced almost thirty years ago by our laboratory and constitutes a highly efficient synthesis of substituted cyclopentanes, tetrahydrofurans, and pyrrolidines. Initial efforts to render the reaction enantioselective relied on the commercially available ligand L1 9 (Figure 1). Unfortunately, although giving high conversion to product, the enantioselection was rather poor (37% ee). Likewise, phosphoramidite ligand L2 9 possessing no chirality in the amine component was largely ineffective for promoting enantioselection. In contrast to these standard phosphoramidites, the cyclic pyrrolidine phosphoramidite ligands L3-5 4 all gave excellent levels of enantioinduction. Various aryl substituents were examined with bis-(4-biphenyl)phosphoramidite ligand L5 attaining near perfect enantioselection in 75% isolated yield (see Table 1 Based on these promising results, an examination of other tropone systems was undertaken (Table 1). To explore the effect of the position of the ester functionality, both the 3-carboethoxy and 2-carboethoxy tropones 7 (3b, 3c) were synthesized. Gratifyingly, both tropones gave comparable reaction yields and excellent diastereo-and enantioselectivity (entries 2 and 3). In both cases, only one [6+3] regioisomer was obtained and followed what was predicted from electronic considerations. 10 We also examined less electron deficient tropones, such as tropone (3d) itself. Although a higher temperature was required to obtain good conversion, the cycloaddition reaction proceeded to give the desired product 4d in good yield, diastereomeric ratio, and enantioselectivity (entry 4).A series of 2-substituted tropones, readily available from tropolone, 11 were also prepared and examined. The reaction of 2-chlorotropone (3e) proceeded very well to give the bicycle 4e in 94% yield and 94 % ee (entry 5). X-ray crystallographic analysis on the 2-chloro TMM adduct 4e unambiguously established both the absolute and relative configuration as depicted. Interestingly, 2-bromotropone failed to give any desired cycloaddition. While 2-methoxytropone also displayed no reactivity, 2-acetoxytropone (3f) delivered cycloadduct 4f, again with excellent yield and enantioinduction (entry 6). Likewise, while 2-dimethylamino tropone was unreactive, 2-phthalimido tropone (3g) was well suited to the reaction conditions, although a slightly diminished ee of 86% was observed (entry 7). These r...

The first total synthesis of (-)-aurafuron A is presented. It features a Suzuki cross-coupling reaction and a high yielding anionic aldol addition as central carbon skeleton building reactions. The synthesis confirms the proposed structure including its configuration and allows for detailed SAR studies.

Here we describe the synthesis of β-lipomycin, a secondary metabolite isolated from the fermentation broth of Corallococcus coralloides. The synthesis relies on the structural assignment made by a statistical method, the so-called profile hidden Markov model. Using this protocol, not only the configuration of the secondary alcohol, but also of the adjacent methyl branch could be deduced. The synthesis therefore not only provides access to this natural product but also confirms the validity of this approach for configurational assignment at methyl branches of modular polyketides.

Wir beschreiben hier die Synthese des aus Corallococcus coralloides isolierten Naturstoffs b-Lipomycin. Die Konfiguration des Zielmoleküls wurde dabei mithilfe eines "Profile-Hidden-Markov"-Modells bestimmt, da sich mit diesem statistischen Ansatz nicht nur die Konfigurationen von sekundären Alkoholen sondern auch die von a-Methylgruppenverzweigungen vorhersagen lassen. Damit liefert die Synthese nicht nur einen praktikablen Zugang zu diesem Naturstoff, sondern bestätigt auch die Gültigkeit des hier verwendeten Modells zur Vorhersage der Konfiguration von a-Methylgruppenverzweigungen in modularen Polyketiden.Hintergrundinformationen zu diesem Beitrag sind im WWW unter http://dx.