P.Moran

A modular design for a novel heterogeneous synergistic catalytic system, which simultaneously activates the electrophile and nucleophile by the combined activation modes of a separate metal and non-metal catalyst, for asymmetric cascade transformations on a solid surface is disclosed. This modular catalysis strategy generates carbocycles (up to 97.5:2.5 er) as well as spirocyclic oxindoles (97.5:2.5 to >99:0.5 er), containing all-carbon quaternary centers, in a highly enantioselective fashion via a one-pot dynamic relay process.

We report a unique mechanism-guided reaction that enhances and expands the chemical space that readily generated gold(I) acetylides currently operate in. Our strategy exploits the propensity of gold(I) carbophilic catalysts with specific counteranions (LAuX – X=triflate or triflimidate) to efficiently activate and desilylate trimethylsilylalkynes, thereby mediating the in situ formation of equal and catalytic quantities of a silyl Lewis acid (TMSX) of tunable strength and a nucleophilic gold(I) acetylide. This unprecedented manifold opens avenues for developing synergistic silyl-gold(I)-catalyzed alkynylation strategies of diverse pro-electrophiles which were heretofore unattainable, the proof of concept being principally exemplified herein with the first catalytic alkynylation of N,O-acetals. The reaction proceeds at low catalyst loading, employs mild reaction conditions, is easily scalable, and affords propargylic lactam products in good to excellent yields. Furthermore, it is fully amenable to a diverse array of structure and function substrates, and also expands to other pro-electrophiles beyond N,O-acetals. Control experiments have been carried out that strongly support our dual reaction mechanism proposal which, furthermore, itself outlines an inextricable link between the strength of the ancillary silyl Lewis acid (TMSOTf versus TMSNTf₂) and the coordinating ability of the gold counter anion employed. This underlying feature of our system underscores its significant potential and flexibility, which indeed manifests with the demonstration that by carefully selecting the gold counter ion, it is possible to manipulate the strength of the ancillary silyl Lewis acid so that it can be tailored to the ionizing ability of a particular pro-electrophile.

A convenient zinc-promoted [4+3] cycloaddition of a carbonyl ene–yne with simple dienes was first achieved. This reaction provided an efficient strategy to prepare various cyclohepta[b]furan rings by cascade cycloadditions. Additionally, a multicomponent reaction of dione, alkynal, and diene was also reported, which exhibited a novel strategy for selective creations of CO bonds and CC bonds.

Go tandem! A first zinc-catalyzed tandem [4+3] cycloaddition is presented herein. Various substituted cyclohepta[b]furans were synthesized from carbonyl ene–yne and diene in moderate to good yield. Furan rings and seven-membered rings were prepared in one single step (see scheme; TBS=tert-butyldimethyl).

A convenient synthetic pathway enabling D-glucal and D-galactal pinacol boronates to be prepared in good isolated yields was achieved. Both pinacol boronates were tested in a series of cross-coupling reactions under Suzuki–Miyaura cross-coupling conditions to obtain the corresponding aryl, heteroaryl, and alkenyl derivatives in high isolated yields. This methodology was applied to the formal synthesis of the glucopyranoside moiety of papulacandin D and the first total synthesis of bergenin.

Building blocks with boron: A convenient synthetic route to D-glucal and D-galactal pinacol boronates was developed, and the boronates were used in cross-coupling reactions to generate the corresponding aryl, heteroaryl, and alkenyl derivatives in high yields (see scheme). This methodology was applied to the formal synthesis of the glucopyranoside moiety of papulacandin D and the total synthesis of bergenin.

We report a BF₃-mediated direct alkynylation of pyridines at C(2) by using a variety of alkynyllithium reagents (oxidative cross-coupling). Moreover, we have developed a novel transition-metal-free cross-coupling method between alkylmagnesium reagents and 4-substituted pyridines, such as isonicotinonitrile and 4-chloropyridine, by employing BF₃⋅OEt₂ as a promoter. The combination of these methods enabled us to efficiently prepare a range of di-, tri-, and tetrasubstituted pyridines.

Oxidative or non-oxidative—That is the question! Pyridines bearing a substituent at position 4 readily undergo a BF₃-mediated oxidative coupling at position 2 with a wide range of alkynyllithium compounds. In contrast, 4-cyano- or 4-chloropyridines undergo a novel BF₃-mediated cross-coupling at position 4 with alkylmagnesium reagents. The combination of the two transition-metal-free procedures allows the preparation of a broad range of pyridines.

The combination of cinchona-alkaloid-derived primary amine and Au^I–phosphine catalysts allowed the selective CH functionalization of two adjacent carbon atoms of pyrroles under mild reaction conditions. This sequential dual activation provides seven-membered-ring-annulated pyrrole derivatives in excellent yields and enantioselectivities.

Outwitted: The combination of cinchona-alkaloid-derived primary amine and Au^I–phosphine catalysts allowed the selective CH functionalization of two adjacent carbon atoms of pyrroles under mild reaction conditions. This sequential dual activation provides seven-membered-ring-annulated pyrrole derivatives in excellent yields and enantioselectivities (see scheme).

The development of a gold(I)-catalyzed sulfination of aryl boronic acids is described. This transformation proceeds through an unprecedented mechanism which exploits the reactivity of gold(I)–heteroatom bonds to form sulfinate anions. Further in situ elaboration of the sulfinate intermediates leads to the corresponding sulfones and sulfonamides, two pharmacophores routinely encountered in drug discovery.

À la mode: A gold(I)-catalyzed synthesis of sulfinates has been accomplished. Preparation of proposed intermediates, X-ray studies, and a number of mechanistic experiments suggest that an unprecedented mode of reactivity for gold(I) has been achieved. The resulting sulfinates from this reaction can be functionalized in situ to form sulfones and sulfonamides.

Herein is described a versatile and broad synergistic strategy for expansion of chemical space and the synthesis of valuable molecules (e.g. carbocycles and heterocycles), with up to three quaternary stereocenters, in a highly enantioselective fashion from simple alcohols (31 examples, 95:5 to >99.5:0.5 e.r.) using integrated heterogeneous metal/chiral amine multiple relay catalysis and air/O₂ as the terminal oxidant. A novel highly 1,4-selective heterogeneous metal/amine co-catalyzed hydrogenation of enals was also added to the relay catalysis sequences.

Relay switch: A versatile strategy for expansion of chemical space and the synthesis of valuable molecules, having up to three quaternary stereocenters, in a highly enantioselective fashion from simple alcohols is described. The method employs integrated heterogeneous metal/chiral amine multiple relay catalysis and air/O₂ as the terminal oxidant.

Three is a lucky number: An enantioselective transformation of allylic alcohols into β-chiral saturated alcohols has been developed by combining two distinct metal- and organocatalyzed catalytic cycles. This waste-free triple cascade process merges an iron-catalyzed borrowing-hydrogen step with an aminocatalyzed nucleophilic addition reaction.

Carbonyl-substituted allenes are highly important synthetic intermediates for a number of heterocycles and strained-ring systems. However, chemistry of allenyl aldehydes has not been explored as extensively as their ketone, ester, or amide analogues because of a lack of general synthetic methods. Described herein is the first direct α-vinylidenation of aldehydes and an α-vinylidenation/γ-functionalization cascade to access tri- and tetrasubstituted allenyl aldehydes using a combination of a gold catalyst and an secondary amine. The reactive enamine intermediate of an aldehyde reacts with the gold-activated hypervalent silylethynyl benziodoxolone to selectively generate the corresponding trisubstituted allenyl aldehyde. The allenyl aldehyde can further react with another equivalent of the alkynylation reagent or other electrophiles to afford tetrasubstituted allenes bearing an aldehyde group, an acetylene, and a halogen functionality. This method enables rapid access to polysubstituted furans from aldehydes.

Gold and amine team up: Gold and an amine catalyst work synergistically to promote either an α-vinylidenation or an α-vinylidenation/γ-functionalization of aldehydes to generate tri- and tetrasubstituted allenes. The allene products also undergo an additional reaction to generate polysubstituted furans.

Radical methods: The title reaction proceeds in the presence of a palladium catalyst to deliver substituted tetrahydrocyclobuta[b]benzofurans in a stereoselective manner (see scheme). A radical mechanism is discussed.