Two-fold tandem acyl-group shift/cyclization via gold catalysis

A complex cascade involving allendiynes in the presence of a cationic gold catalyst is described. The process features two sequential acyl-group shift/cyclization steps eventually delivering a bicyclic furan derivative from the acyclic precursor. A controlled sequence of molecular events can thus readily deliver the desired heterocycle with a remarkable selectivity.


Introduction
The synthesis of functionalized cyclic frameworks in a concise fashion has always been of particular interest for synthetic chemists in their continuing effort to disclose new reactivities and more efficient methodologies. 1,359][20] Recently, a straightforward access to polyconjugated bis-enones has been reported by our group via a gold-catalyzed tandem 1,3-acyloxy migration/cyclization/1,5-acyl-shift of linear diynes (Scheme 1). 21

Scheme 1. Access to conjugated bis-enones via gold catalysis
We asked ourselves whether it would be possible to increase the already remarkable complexity of the sequence by testing this methodology on substrates bearing an allene functionality in place of the unreacted alkene in the above depicted reaction (Scheme 1).

Results and Discussion
Our study focused on a suitable diyne substrate 5 bearing an allenyl ester (Scheme 2).Synthesis of this acyclic precursor was realized from pent-4-yn-1-ol (1), which was monosilylated at the acetylenic position by double deprotonation with n-butyllithium, addition of two equivalents of trimethylsilyl chloride and subsequent treatment with aqueous HCl.Oxidation of the resulting alcohol with pyridinium chlorochromate delivered aldehyde 2. This aldehyde was then treated with deprotonated phenylacetylene to furnish a propargylic alcohol that was next esterified using bromoacetyl bromide to give diyne 3. Reaction with triphenylphosphine followed by base treatment furnished the phosphorus ylide 4, which was employed in the next step without purification.3][24][25][26][27] Allenoyl derivative 4 could thus be obtained in 80% yield from -bromoester 3. Final desilylation by means of potassium fluoride delivered 5 possessing the desired terminal triple bond in 63% yield.
We then examined the reactivity of 5 in the presence of catalytic amounts (4 mol%) of Echavarren's cationic gold(I) catalyst 28 in dichloromethane at room temperature, conditions that proved to be optimal in our previous study.We were delighted to observe the sole formation of furan derivative 6, which also readily occurred with only 2 mol% of the catalyst without hampering substrate conversion.Product 6 could thus be obtained in a good 74% isolated yield.Further reduction of catalyst loading leads however to sluggish reactions.The selective incorporation of the allene fragment in the heterocyclic skeleton of 7 (see below for the mechanistic discussion) proves the feasibility of further expanding the molecular complexity achievable within these cascades in a controlled manner.Providing a mechanistic rationale for this reaction was straightforward in view of previous studies by us and others (Scheme 5).
0][31] The cationic gold catalyst then coordinates to the least hindered unsaturation, namely the terminal alkyne fragment, triggering the cyclization of the most electron-rich allene in 7-Au.The favored 5-exo-dig process delivers vinylgold intermediate 8 that can subsequently evolve to 9 via a 1,5-acyl transfer (Cycle II in Scheme 4).According to previous double-tagging experiments 21 employing deuterated substrates, this step presumably occurs through an intramolecular mechanism.The stereoselectivity of the acyl transfer has been modeled via DFT on simplified substrates and revealed the energetic convenience of formation of 9 in a concerted, asynchronous fashion in respect to its opposite isomer owing to reduced steric congestion.Likely, replacing the acyl group used for modeling with a more sterically demanding allene will increase the formation of 9 possessing the (E)-exocyclic double bond.3] A similar reactivity of allenones has been recently reported by Alcaide and Almendros for the synthesis of 2-substituted furans via Au(I) catalysis. 34Propargylic allenols The overall selectivity of this cascade is indeed outstanding reasoning on the sequential order of molecular events that readily takes place.Within the same molecule, three different C-C multiple bonds are activated by the gold catalyst through three distinct catalytic cycles, in a sequential order (alkyne-alkyne-allene) to afford ultimately the heterocyclic product.

Conclusions
A concise conjugated furan synthesis of has been developed by means of cationic gold catalysis.The complex sequence generates the bicyclic product via a two-fold sequential acyl group migrations/cyclizations steps.Careful tuning of the stereoelectronic properties of the substrates makes then possible to achieve high molecular complexity in one pot and with remarkable selectivity.

Experimental Section
Unless specially mentioned all reactions were carried out under an anhydrous argon atmosphere in flame-dried glassware.Reagents were purchased from commercial sources and used as received.Solvents were systematically distilled using standard procedures and degassed prior to use.