Gold‐catalysed oxidative cyclisation reactions of ynamides offer great promise in γ‐lactam synthesis but are limited by preferential over‐oxidation to form α‐keto imides. Evaluating the factors that might limit N‐cyclisation pathways led to effective gold‐catalysed conditions that allow access to different fused γ‐lactams on changing the ynamide N‐substituent and accommodate previously incompatible substitution patterns. New and efficient methods for the synthesis of functionalised 3‐aryl indoles and cyclohepta[c]pyrrol‐1‐one derivatives are presented. These conditions illustrate the complementarity of gold catalysis to other metals.
The intermolecular addition of 1,3-dicarbonyl equivalents to endoperoxides in the presence of an organocatalyst yields trans-fused butyrolactones in high yield and enantioselectivities. This methodology expands the synthetic utility of endoperoxides and further underlines their potential as sources of oxygen functionality for natural and non-natural product target synthesis. The oxidation of dienes to yield endoperoxides represents a selective and green chemical method for introducing oxygen functionality within a substrate. 1 However, conversion of these endoperoxide products into useful asymmetric building blocks 1c,2 for natural and non-natural product target synthesis, without the use of toxic transition metals, has yet to be fully exploited. For example, Taylor and co-workers in 2002 reported the conversion of endoperoxides (1) into useful butyrolactones (2) via an intermediary cis-γ-hydroxy-enone (3) (Scheme 1); however, they were only able to achieve this in an enantioselective fashion using a Co(II) catalyst and no asymmetric examples of bicyclic endoperoxides were included in their study, 2g presumably due to the reactivity of bicyclic endoperoxides with Co(II) salts which traditionally delivers the bisepoxide products. 3 In 2006, Toste and co-workers successfully desymmetrised bicyclic endoperoxides (4) using an organocatalytic Kornblum-De La Mare rearrangement; 4 however, the synthetic use of these highly enantio-enriched hydroxyenone products (5) has been limited. 5 In a project aimed at investigating the anti-inflammatory activity of trans-fused xanthanolide natural product analogues, 6 we recently required access to enantioenriched trans-fused butyrolactones (7) which we envisaged could be obtained from endoperoxides (6) (Scheme 1). While enantioselective routes toward cis-fused butyrolactones exist 6c-i general synthetic routes toward trans-fused butyrolactones are less common; e.g. in Shishido's first asymmetric synthesis of the anti-inflammatory natural product xanthatin, 6j they had to convert a key cis-lactone precursor 6k into the trans-lactone using a 3-step procedure which included a Mitsunobu inversion of the crucial hydroxyl group. Scheme 1. Planned route toward trans-fused butyrolactones. Key to this approach is the trapping of a cyclic hydroxyenone, a result of the based catalysed rearrangement of endoperoxides, by a 1,3dicarbonyl equivalent which we envisaged would occur via an intermolecular 1,4-conjugate addition pathway. 2g Furthermore, since hydroxy enones such as 5 can be obtained via an organocatalysed Kornblum-De La Mare 4,7 rearrangement of endoperoxides this approach would represent an asymmetric protocol for generating complex trans-fused butyrolactone scaffolds from endoperoxides, which in turn can be obtained from simple 1 O2 oxidation of dienes. After initial optimisation studies 9 we found treatment of endoperoxide 4 8 in THF 9 in the presence of 10 mol% of catalyst 8a for a 16h period followed by addition diethylsodiomalonate gave the desired lactone (-)-9a in an isolated...
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