Construction of cyclic enones via gold-catalyzed oxygen transfer reactions

During the last decade, gold-catalyzed reactions have become a tour de force in organic synthesis. Recently, the gold-, Brønsted acid- or Lewis acid-catalyzed oxygen transfer from carbonyl to carbon–carbon triple bond, the so-called alkyne–carbonyl metathesis, has attracted much attention because this atom economical transformation generates α,β-unsaturated carbonyl derivatives which are of great interest in synthetic organic chemistry. This mini-review focuses on the most recent achievements on gold-catalyzed oxygen transfer reactions of tethered alkynones, diynes or alkynyl epoxides to cyclic enones. The corresponding mechanisms for the transformations are also discussed.

During the early years of this century, organic chemists became aware that gold salts or complexes were highly active catalysts in homogeneous catalysis because of the strong π-and σ-electrophilicity of gold [28][29][30][31][32][33]. Since then, the number of new gold-catalyzed reactions reported in the literature has increased substantially and gold catalysis has become one of the hottest research fields in synthetic organic chemistry [34][35][36][37][38][39][40][41][42]. Due to their unique alkynophilicity, gold catalysts are especially suited to the activation of carbon-carbon triple bonds.
Gold-catalyzed formation of cyclic enones from alkynyl ketones Yamamoto and co-workers were the first to report the goldcatalyzed formation of conjugated cyclic enones under mild conditions using tethered alkynyl ketones as substrates (Scheme 2) [43]. Both, aromatic and aliphatic groups substituted on alkynyl ketones 1 were investigated in this reaction, and the corresponding enone products 2 were isolated in good yields. They employed the alkyne-carbonyl metathesis in the preparation of fused ring systems and obtained two sixmembered bicyclic products. However, if the original ring was five-or eight-membered, the reaction produced β,γ-unsaturated bicyclic enones rather than their α,β-unsaturated counterparts.
Yamamoto and co-workers proposed a [2 + 2] mechanism for their gold-catalyzed cyclization of alkynyl ketones (Scheme 3). In their mechanism, the carbonyl group attacks the gold activated triple bond to form an oxonium intermediate, which then generates an oxetenium intermediate. After several electron transfer steps, the cyclic enone product is formed. A similar [2 + 2] pathway has also been invoked for the Brønsted acid-or Lewis acid-mediated intramolecular and intermolecular alkyne-aldehyde metatheses. If terminal alkynyl ketone 3 is employed as the substrate, the reaction still furnishes α,β-unsaturated cyclic enone 4, but it necessitates a larger catalyst load (Scheme 4). By carefully monitoring of the reaction, it was found that intermediate 5 was This gold-catalyzed cyclization of alkynyl ketones to enones was successfully utilized in a cascade reaction by the same authors (Scheme 5) [44]. Using enynones 7 as the substrate, the gold-catalyzed tandem alkyne-carbonyl metathesis/Nazarov reaction generated a number of intriguing fused bicyclic, tricyclic and tetracyclic derivatives of 8 in moderate to good yields and excellent diastereoselectivity. In this case, the gold catalyst exhibited a dual role, namely the activation of alkyne and carbonyl moieties.
Yamamoto and co-workers attempted to utilize their protocol to build five-membered cyclic enones, however, when they employed alkynyl ketone 9 as the substrate, the gold catalyst did not show good activity, and less than 30% of the desired Scheme 4: Gold-catalyzed cyclization of terminal alkynyl ketones.
product 10 was formed [45]. After optimizing the reaction conditions, the authors found that TfOH was the best catalyst for this oxygen transfer reaction in methanol (Scheme 6). This TfOH-mediated cyclization was applied to the synthesis of various fused tricyclic and tetracyclic derivatives of 10. Hammond and co-workers found that the gold-catalyzed oxygen transfer reaction proceeded very smoothly when using alkynyldiketone 11 as the substrate (Scheme 7) [46]. Indeed, this reaction was complete in 5 minutes at room temperature to give the five-membered cyclic enones 12 cleanly and in excellent yields. The large reactivity difference between substrates 9 and 11 prompted the authors to propose an alternative [4 + 2] mechanism for this transformation, rather than the previously proposed and well-accepted [2 + 2] pathway for oxygen transfer reactions.
An isotopic labeling experiment was designed to elucidate the pathway responsible for the gold-catalyzed intramolecular oxygen transfer of 2-alkynyl-1,5-diketones (Scheme 8). By introducing an 18 O atom into one of the carbonyls of the substrate, and using the 13 C NMR spectra of the substrate and product to locate the 18  Chan and co-workers developed a gold-catalyzed tandem intramolecular rearrangement of alkynyl arylaldehydes 13 to benzoxepinones 14 with good regioselectivity (Scheme 11) [47]. This transformation was effectively promoted by the addition of benzyl alcohol and the sequential addition of p-toluenesulfonic acid. However, in the absence of p-toluenesulfonic acid, benzyl ether 15 was isolated as the major product. The latter was considered to be an intermediate in the reaction and moreover, the isolated compound 15 could be transformed into the final product 14 under the mediation of p-toluenesulfonic acid.

Gold-catalyzed formation of cyclic enones from diynes
Zhang and co-workers reported gold-catalyzed cyclizations to cyclohexenones 17, employing terminal 1,6-diynes 16 as substrates in the presence of a Brønsted acid and 1 equiv of water (Scheme 12) [48]. None of the desired products were obtained in the absence of the gold catalyst, the Brønsted acid or water. Interestingly, when the diacid 1,6-diyne (R 1 = R 2 = COOH) was employed in the reaction, only the esterified product (R 1 = R 2 = COOMe) was isolated, albeit in low yield. The authors also carried out this gold-catalyzed transformation in an ionic liquid [49]. This modification enabled the separation of the gold catalyst from the organic mixture and the recovered gold catalyst in the ionic liquid was re-used as many as five times without loss of activity.

Scheme 12: Gold-catalyzed cyclization of terminal diynes.
A hydrolysis/cyclization mechanism was proposed for the transformation (Scheme 13). Although this mechanism is plausible, another option for the cyclization step might exist. One of the key intermediates in the catalytic cycle is the hydrolyzed product -the alkynyl ketone from hydrolysis of one triple bondwhich is the same as the substrate that was employed by Yamamoto and co-workers. Thus, a similar diketone intermediate 6' could also have been formed before being transformed into the final product via intramolecular aldol condensation.
Fiksdahl and co-workers investigated a similar gold-catalyzed transformation of internal 1,6-diynes 18 in methanol at room temperature (Scheme 14) [50,51]. Interestingly, a non-conjugated five-membered cyclic enone 19 was isolated as the product, instead of the conjugated cyclohexenone that was obtained from terminal 1,6-diynes. However, the scope of this transformation was limited to just a few substituent variations on the alkynes. When both R 1 and R 2 were ethyl groups, this cycliza- tion was dramatically retarded and only traces of the desired product were obtained. Under the mediation of aluminium oxide, this non-conjugated cyclopentylidene ketone product isomerized to the conjugated cyclopentenyl ketone 20.
The authors proposed a solvolysis/cyclization mechanism for this gold-catalyzed cyclization, which was supported by a deuterium isotopic experiment (Scheme 15). Two molecules of methanol were involved in the transformation and a dimethoxyketal intermediate was formed: The final product was derived from the hydrolysis of this ketal intermediate. When  Gold-catalyzed formation of cyclic enones from alkynyl epoxides Hashmi and co-workers synthesized a number of 2-alkynyl aryl epoxides 21 intended to be used as substrates for a goldcatalyzed rearrangement to naphthols. Surprisingly, acylindene 22 turned out to be the product of this reaction, rather than the expected naphthol (Scheme 16) [52]. However, when a bulky group was substituted on the triple bond, this gold-catalyzed transformation was completely suppressed. Moreover, none of the desired product could be obtained when a terminal alkyne, a TMS-substituted alkyne, or even an ester-substituted epoxide was used as the starting material.
An 18 O isotopic experiment helped the authors to propose an intramolecular oxygen transfer mechanism for the above transformation (Scheme 17). When employing the 18 O incorporated substrate in the reaction, the authors found that the isolated product still contained the isotopic atom which excludes the involvement of external water in the reaction. A cross-over experiment with a mixture of two substrates (one with 18 O, the other without) was also conducted, and no 18 O scramble was found in the products, which clearly supported the intramolecular nature of the oxygen transfer. Liu and co-workers independently reported a very similar goldcatalyzed cyclization of 2-alkynyl aryl epoxide 21 to acylindene 22 (Scheme 18) [53]. A deuterium isotopic experiment was conducted to support the intramolecular oxygen transfer mechanism. However, when a trisubstituted epoxide 23 was employed in the reaction, the gold catalyst did not promote the transformation. By contrast, when AgSbF 6 was used as the catalyst, the 1,2-alkyl shifted product 24 was obtained.

Conclusion
This short review compiles recently reported gold-catalyzed oxygen transfer reactions used to build cyclic enones from tethered alkynyl ketones, 1,6-diynes or 2-alkynyl aryl epoxides. Most of these reactions take place under mild conditions and the corresponding products were isolated in good yields. The mechanisms for these transformations were also comparatively Scheme 18: Gold or silver-catalyzed cyclization of alkynyl epoxides and the corresponding deuterium labeling experiment.
discussed. Similar Brønsted acid or other metal mediated transformations and their applications to cascade cyclizations were additionally described. Given gold's strong π-electrophilicity, it is expected that novel applications of gold catalysts in reactions of alkynes, allenes, and even alkenes, will continue to attract the attention of synthetic chemists.