Nickel Catalysis: Synergy between Method Development and Total Synthesis.

Nickel(0) catalysts have proven to be powerful tools for multicomponent coupling reactions in our laboratories over the past 15 years. This interest was originally sparked by the ubiquity of allylic alcohol motifs in natural products, such as (-)-terpestacin, which we envisioned assembling by the coupling of two π components (alkyne and aldehyde) with concomitant reduction. Mechanistic investigations allowed us to elucidate several modes of controlling the regioselectivity and stereoselectivity in the oxidative cyclization, and these insights enabled us to leverage combinations of alkenes and phosphine ligands to direct regioselective outcomes. The initial success in developing the first intermolecular reductive alkyne-aldehyde coupling reaction launched a series of methodological investigations that rapidly expanded to include coupling reactions of alkynes with other electrophilic π components, such as imines and ketones, as well as electrophilic σ components, such as epoxides. Aziridines proved to be more challenging substrates for reductive coupling, but we were recently able to demonstrate that cross-coupling of aziridines and alkylzinc reagents is smoothly catalyzed by a zero-valent nickel/phenanthroline system. Moreover, the enantioselective alkyne-aldehyde coupling and the development of novel P-chiral ferrocenyl ligands enabled the total synthesis of (-)-terpestacin, amphidinolides T1 and T4, (-)-gloeosporone, and pumiliotoxins 209F and 251D. We subsequently determined that alkenes could be used in place of alkynes in several nickel-catalyzed reactions when a silyl triflate activating agent was added. We reason that such an additive functions largely to enhance the electrophilicity of the metal center by coordination to the electrophilic π component, such that less nucleophilic alkene π donors can undergo productive combination with nickel complexes. This activation manifold was further demonstrated to be effective for alkene-aldehyde couplings. In a related manner, electrophilic promoters were also successfully employed for allylic substitution reactions of allylic carbonates with simple alkenes and in the Mizoroki-Heck reaction of both benzyl and aryl electrophiles. In these instances, it is proposed that counterion exchange from a more strongly coordinating anion to the weakly or noncoordinating triflate counterion enables reaction at an electrophilic Ni(II) center rather than by coordination to one of the coupling components. Mechanistic insights also played an important role in the development of mixed N-heterocyclic carbene/phosphite ligand systems to overcome challenges in regioselective alkene-aldehyde coupling reactions. We hope that, taken together, the body of work summarized in this Account demonstrates the constructive interplay among total synthesis, methodological development, and mechanistic investigation that has driven our research program.

A General Strategy for the Synthesis of Enantiomerically Pure Azetidines and Aziridines through Nickel-Catalyzed Cross-Coupling.

In this communication, we report a straightforward synthesis of enantiomerically pure 2-alkyl azetidines. The protocol is based on a highly regioselective nickel-catalyzed cross-coupling of aliphatic organozinc reagents with an aziridine that features a tethered thiophenyl group. Activation by methylation transforms the sulfide into an excellent leaving group and triggers the formation of the 2-substituted azetidine core structure by cyclization. In addition, we have expanded this concept to the synthesis of enantiomerically pure, terminal alkyl aziridines. Coupling of a TMS-protected aziridine alcohol, followed by acidic work-up to remove the silyl group, provides 1,2-amino alcohol products that are readily cyclized to aziridines. Both of these sequences display excellent functional group tolerance and deliver the desired azetidine and aziridine products in good to excellent yields.

Highly regioselective nickel-catalyzed cross-coupling of N-tosylaziridines and alkylzinc reagents.

Herein, we report the first ligand-controlled, nickel-catalyzed cross-coupling of aliphatic N-tosylaziridines with aliphatic organozinc reagents. The reaction protocol displays complete regioselectivity for reaction at the less hindered C-N bond, and the products are furnished in good to excellent yield for a broad selection of substrates. Moreover, we have developed an air-stable nickel(II) chloride/ligand precatalyst that can be handled and stored outside a glovebox. In addition to increasing the activity of this catalyst system, this also greatly improves the practicality of this reaction, as the use of the very air-sensitive Ni(cod)2 is avoided. Finally, mechanistic investigations, including deuterium-labeling studies, show that the reaction proceeds with overall inversion of configuration at the terminal position of the aziridine by way of aziridine ring opening by Ni (inversion), transmetalation (retention), and reductive elimination (retention).

On the mechanism of the organocatalytic asymmetric epoxidation of α,ß-unsaturated aldehydes.

Mechanistic studies on the organocatalytic epoxidation of α,ß-unsaturated aldehydes explore the autoinductive behavior of the reaction and establish that the hydrate/peroxyhydrate of the product is acting as a phase-transfer catalyst. Based on these studies, an improved methodology that provides high selectivities and decreased catalyst loading, through the addition of chloral hydrate, is developed.

Selective access to both diastereoisomers in an enantioselective intramolecular Michael reaction by using a single chiral organocatalyst and application in the formal total synthesis of (-)-epibatidine.

Two in one: Both diastereoisomers of 4-nitro-3-substituted cyclohexanones are accessed selectively by an intramolecular Michael reaction using a single chiral aminocatalyst (see scheme). Mechanistic studies show that the reaction is selective for the cis-diastereoisomer and that the trans-diastereoisomer arises over time. DFT calculations suggest that the cis-selectivity is due to a favorable electrostatic interaction between the iminium ion and the nucleophile.

Asymmetric synthesis of γ-nitroesters by an organocatalytic one-pot strategy.

An enantioselective synthesis of γ-nitroesters by a one-pot asymmetric Michael addition/oxidative esterification of α,ß-unsaturated aldehydes is presented. The procedure is based on merging the enantioselective organocatalytic nitroalkane addition with an N-bromosuccinimide-based oxidation. The γ-nitroesters are obtained in good yields and enantioselectivities, and the method provides an attractive entry to optically active γ-aminoesters, 2-piperidones, and 2-pyrrolidones.

The diarylprolinol silyl ether system: a general organocatalyst.

The past few decades have witnessed some of the most important and revolutionizing advances in the field of asymmetric catalysis. Chemists no longer rely solely on natural sources as the starting point of their synthetic strategy, as in chiral pool or auxiliary-based synthesis. Instead, naturally occurring chiral motifs are selected and, either unchanged or after modification, used in substoichiometric amounts as chiral catalysts or ligands. In this way, they effectively transfer their chirality to prochiral substrates, thereby rapidly amplifying and diversifying the arsenal of useful chiral building blocks available to the synthetic community. A long-standing goal in the pursuit of new catalytic systems is the discovery of general catalysts. Ideally, such catalytic systems should be capable of promoting a large number of enantioselective reactions, via multiple modes of activation, with good substrate tolerance and high stereoselectivity. In this Account, we describe the synthetic usefulness, efficiency, selectivity, and robustness of the diarylprolinol silyl ether system as the catalyst in various reactions of aldehydes. Based on the diarylprolinol silyl ether system, several studies on enamine-mediated transformations of saturated aldehydes have resulted in the introduction of different functionalities into the α-position of aldehydes in a highly stereoselective manner. This HOMO-activation concept was later extended to include α,ß-unsaturated aldehydes, which after condensation with the aminocatalyst generate a dienamine species capable of undergoing stereoselective Diels-Alder-type reactions. As a result, the effective functionalization of the γ-position of the aldehyde is achieved. Recently, the activation principle was further developed to include 2,4-dienals, which form trienamine intermediates upon condensation with the aminocatalyst. The trienamines effectively react with carbon-centered dienophiles, forming aldehyde products having up to four contiguous stereocenters. Because of the concerted nature of the reaction and the efficient catalyst shielding of the ß-position, the stereoinduction is achieved at the remote ε-position of the original aldehyde. Complementary to the enamine-mediated activations, α,ß-unsaturated aldehydes can also be efficiently functionalized by applying the diarylprolinol silyl ether system via conjugate addition through iminium-ion-mediated processes, that is, LUMO-activation. In such reactions, the aminocatalyst not only effectively shields one of the enantiotopic faces of the enal, it also ensures excellent chemoselectivity, affording 1,4-adducts as the only products. Several different carbon and heteroatom nucleophiles can be added in a highly stereoselective fashion. The ability of the catalysts to participate in various enamine- and iminium-ion-mediated processes also makes them ideal for the sequential addition of nucleophiles and electrophiles in a cascade manner. These cascade reactions thereby afford access to products having at least two stereocenters. In the years to come, the diarylprolinol silyl ether catalysts will probably maintain their prominent position as general catalysts in the field of aminocatalysis. Moreover, recent efforts devoted to mechanistic studies might soon engender further advances with this versatile catalytic system, particularly in the areas of activation modes, catalyst loadings, and industrial applications.

Organocatalytic iminium ion/carbene reaction cascade for the formation of optically active 2,4-disubstituted cyclopentenones.

An organocatalytic iminium ion/N-heterocyclic carbene (NHC) cascade reaction between ß-keto phenyltetrazolesulfones and α,ß-unsaturated aldehydes, providing direct access to optically active 2,4-disubstituted cyclopent-2-enones, has been developed. The products are isolated in good yields with high enantioselectivities.

Asymmetric organocatalytic synthesis of complex cyclopenta[b]quinoline derivatives.

An efficient one-pot procedure that provides a direct access to polycyclic hexahydrocyclopenta[b]quinoline derivatives having five stereogenic centers has been developed. The system displays great tolerance toward different aldehydes, anilines, and nitroalkenes. The products are obtained in high yields and excellent enantio- and diastereoselectivities.

Synthesis of 1,2,4-triazolines: base-catalyzed hydrazination/cyclization cascade of α-isocyano esters and amides.

A convenient, efficient synthesis of 1,2,4-triazolines from α-isocyano esters/amides and azodicarboxylates is presented. The developed reaction cascade is based on a base-catalyzed hydrazination-type reaction followed by a subsequent cyclization providing the triazolines in good to excellent yields (75-99%). Phosphine-catalyzed and preliminary asymmetric phase-transfer catalysis approaches have also been investigated.

Pandemic influenza 1918 H1N1 and 1968 H3N2 DNA vaccines induce cross-reactive immunity in ferrets against infection with viruses drifted for decades.

BACKGROUND: Alternative influenza vaccines and vaccine production forms are needed as the conventional protein vaccines do not induce broad cross-reactivity against drifted strains. Furthermore, fast vaccine production is especially important in a pandemic situation, and broader vaccine reactivity would diminish the need for frequent change in the vaccine formulations. OBJECTIVE: In this study, we compared the ability of pandemic influenza DNA vaccines to induce immunity against distantly related strains within a subtype with the immunity induced by conventional trivalent protein vaccines against homologous virus challenge. METHODS: Ferrets were immunised by particle-mediated epidermal delivery (gene gun) with DNA vaccines based on the haemagglutinin (HA) and neuraminidase (NA) and/or the matrix (M) and nucleoprotein genes of the 1918 H1N1 Spanish influenza pandemic virus or the 1968 H3N2 Hong Kong influenza pandemic virus. The animals were challenged with contemporary H1N1 or H3N2 viruses. RESULTS: We demonstrated that DNA vaccines encoding proteins of the original 1918 H1N1 pandemic virus induced protective cross-reactive immune responses in ferrets against infection with a 1947 H1N1 virus and a recent 1999 H1N1 virus. Similarly, a DNA vaccine, based on the HA and NA of the 1968 H3N2 pandemic virus, induced cross-reactive immune responses against a recent 2005 H3N2 virus challenge. CONCLUSIONS: DNA vaccines based on pandemic or recent seasonal influenza genes induced cross-reactive immunity against contemporary virus challenge as good as or superior to contemporary conventional trivalent protein vaccines. This suggests a unique ability of influenza DNA to induce cross-protective immunity against both contemporary and long-time drifted viruses.

Asymmetric one-pot sequential organo- and gold catalysis for the enantioselective synthesis of dihydropyrrole derivatives.

A direct asymmetric one-pot synthesis of optically active 2,3-dihydropyrroles from propargylated malononitrile and N-Boc-protected (Boc = tert-butoxycarbonyl) imines is presented. The approach is based on a bifunctional organocatalytic Mannich-type reaction and a subsequent gold-catalyzed alkyne hydroamination and isomerization. The compatibility of both catalytic systems is presented and the overall transformation results in good yields (up to 70 %) with high selectivities (endo/exo > 10:1) and enantioselectivities (up to 88 % ee). The absolute configuration of the final products is unambiguously established by X-ray analysis. To highlight the synthetic potential of the accessed heterocyclic compounds, their transformation into 1-pyrrolines, which represent direct precursors of pyrrolidines, is presented.

Target-directed organocatalysis: a direct asymmetric catalytic approach to chiral propargylic and allylic fluorides.

A simple, direct one-pot organocatalytic approach to the formation of optically active propargylic fluorides is presented. The approach is based on organocatalytic alpha-fluorination of aldehydes and trapping and homologation of the intermediate providing optically active propargylic fluorides in good yields and enantioselectivities up to 99% ee. The procedure takes place by addition of NFSI, in the presence of 2-[bis(3,5-bis-trifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine (as low as 0.25 mol %) as the catalyst, to aldehydes in combination with dimethyl 2-oxopropylphosphonate and 4-acetamidobenzenesulfonyl azide. The scope of the reaction is demonstrated by the formation of a number of optically active propargylic fluorides. It is also shown that optically active fluoro-containing triazoles can be obtained in one-pot procedures from aldehydes using click-chemistry. Furthermore, important coupling and multicomponent reactions of the optically active propargylic fluorides can be performed without affecting the enantiomeric excess. The direct one-pot formation of optically active allylic fluorides from aldehydes is also demonstrated. Finally, the mechanisms for both the formation of the propargylic and allylic fluorides are outlined.

Direct vinylation and difluorovinylation of arylboronic acids using vinyl- and 2,2-difluorovinyl tosylates via the Suzuki-Miyaura cross coupling.

General reaction conditions were developed for the Pd(0)-catalyzed Suzuki-Miyaura coupling reaction of aryl boronic acids with a simple electrophilic vinylation reagent, vinyl tosylate, providing access to styrene derivatives in good yields. The easily accessible vinyl tosylate represents a stable and less toxic alternative to the vinyl halides and the triflate/nonaflate derivatives. Furthermore, this methodology was expanded to provide a facile and straightforward approach for the introduction of a gem-difluorovinyl substituent onto an aromatic ring using the similar and also readily available 2,2-difluorovinyl tosylate as the electrophilic complement.