Investigation of a dialkylation approach for enantioselective construction of vicinal quaternary stereocenters

A detailed study of the dialkylation of dianions derived from dihydroisoindigo 1 with enantiopure ditriflate 2 is reported. The LHMDS-mediated process has been optimized to give C(2)-symmetric product 3 with high selectivity (C(2) selectivity 3:5 = 100:1; C(2):C(1) selectivity = 8:1). Stereoselection in the C(2) manifold is determined in both the bimolecular and intramolecular alkylation steps.     

Catalytic enantioselective construction of quaternary stereocenters by direct vinylogous Michael addition of deconjugated butenolides to nitroolefins

A direct vinylogous Michael reaction of γ-substituted deconjugated butenolides with nitroolefins has been developed with the help of a newly identified quinine-derived bifunctional catalyst, allowing the synthesis of densely functionalized products with contiguous quaternary and tertiary stereocenters in excellent yield with perfect diastereoselectivity (>20:1 dr) and high enantioselectivity (up to 99:1 er).     

Synthetic studies on perophoramidine and the communesins: construction of the vicinal quaternary stereocenters

An efficient synthetic strategy for installation of the two vicinal quaternary carbon centers of the communesins is reported. Key steps include the O-allylation/Claisen rearrangement of spirolactone systems, which are formed by tandem intramolecular Heck cyclization/carbonylation. Substituent and solvent effects on the stereochemical outcome of the Claisen rearrangements have been examined. The stereochemical assignment of the allyl spirolactone previously reported as 17 has now been revised to 31, which has the communesin relative configuration at the quaternary carbons. Key C-allyl spirolactone 59 bearing functional handles required for the communesin core has been constructed with a 9.8:1 diastereomer ratio.     

Catalytic enantioselective construction of all-carbon quaternary stereocenters: synthetic and mechanistic studies of the C-acylation of silyl ketene acetals

With the aid of an appropriate chiral catalyst, acyclic silyl ketene acetals react with anhydrides to furnish 1,3-dicarbonyl compounds that bear all-carbon quaternary stereocenters in good ee and yield. Mechanistic studies provide strong support for a catalytic cycle that involves activation of both the electrophile (anhydride --> acylpyridinium) and the nucleophile (silyl ketene acetal --> enolate).     

Intramolecular [4 + 2] cycloaddition of nitroalkenes for construction of vicinal quaternary stereocenters

[chemical reaction: see text]. Nitroalkene (E)-1 has been synthesized to test the feasibility of an intramolecular [4 + 2] cycloaddition in a planned synthesis of daphnilactone B. This nitro olefin contains two unique structural features, a nitromethylene lactone and a pendant diene, that combine under the action of SnCl4 in a highly selective fashion to afford nitronates 2a and 2b. These products represent the correct relationship for the vicinal quaternary stereogenic centers in the core of daphnilactone B.     

Construction of polycyclic structures with vicinal all-carbon quaternary stereocenters via an enantioselective photoenolization/Diels–Alder reaction

All-carbon quaternary stereocenters are ubiquitous in natural products and significant in drug molecules. However, construction of all-carbon stereocenters is a challenging project due to their congested chemical environment. And, when vicinal all-carbon quaternary stereocenters are present in one molecule, they will dramatically increase its synthetic challenge. A chiral titanium promoted enantioselective photoenolization/Diels–Alder (PEDA) reaction allows largely stereohindered tetra-substituted dienophiles to interact with highly active photoenolized hydroxy-o-quinodimethanes, delivering fused or spiro polycyclic rings bearing vicinal all-carbon quaternary centers in excellent enantiomeric excess through one-step operation. This newly developed enantioselective PEDA reaction will inspire other advances in asymmetric excited-state reactions, and could be used in the total synthesis of structurally related complex natural products or drug-like molecules for drug discovery.

An enantioselective PEDA reaction was developed to enable stereohindered dienophiles to interact with transient photoenolized hydroxy-o-quinodimethanes, delivering fused or spiro polycyclic rings bearing 2–3 vicinal all-carbon quaternary centers in good yield and excellent ee.     

Highly enantioselective hydrovinylation of alpha-alkyl vinylarenes. an approach to the construction of all-carbon quaternary stereocenters

The highly enantioselective hydrovinylation of alpha-alkyl vinylarenes was realized by using nickel complexes of chiral spiro phosphoramidite ligands. The method provided a new approach to the construction of chiral all-carbon quaternary centers.     

Catalytic enantioselective synthesis of vicinal dialkyl arrays

With a consecutive "asymmetric allylic alkylation (AAA)/cross-metathesis (CM)/conjugate addition (CA)" protocol it is possible to synthesize either stereoisomer of compounds containing a vicinal dialkyl array with excellent stereoselectivity. The versatility of this protocol in natural product synthesis is demonstrated in the preparation of the ant pheromones faranal and lasiol.     

Total synthesis of complex cyclotryptamine alkaloids: stereocontrolled construction of quaternary carbon stereocenters

Our ability to access the more complex members of the cyclotryptamine family of alkaloids, and to exploit their disparate biological activities, is limited by the synthetic challenge posed by their oligomeric, polyindoline structures. A recurring structural theme within these molecules is the presence of multiple quaternary stereocenters in close proximity to one another. Over the last decade, we have developed a set of transformations that allow rapid access to polyindolines, a number of which exploit the ability of catalytic levels of palladium to orchestrate carbon-carbon bond formation with impressive levels of regio- and stereocontrol. This review tells the story behind the development of this toolbox of synthetic methods, and their validation through the total synthesis of a number of structurally complex cyclotryptamine alkaloids. It also highlights an aspect of asymmetric catalysis that has received little attention, the ability of catalytic asymmetric reactions to selectively elaborate complex, polyfunctional molecules.     

Catalytic enantioselective synthesis of fluoromethylated stereocenters by asymmetric hydrogenation

Fluoromethyl groups possess specific steric and electronic properties and serve as a bioisostere of alcohol, thiol, nitro, and other functional groups, which are important in an assortment of molecular recognition processes. Herein we report a catalytic method for the asymmetric synthesis of a variety of enantioenriched products bearing fluoromethylated stereocenters with excellent yields and enantioselectivities. Various N,P-ligands were designed and applied in the hydrogenation of fluoromethylated olefins and vinyl fluorides.

Herein, a catalytic asymmetric hydrogenation to synthesize various products bearing fluoromethylated stereocenters has been developed.     

Synthetic studies towards daphniyunnine B: Construction of AC bicyclic skeleton with two vicinal all carbon quaternary stereocenters

The AC bicyclic skeleton of daphniyunnine B with the required two vicinal all carbon quaternary stereocenters (C-5 and C-8) was accomplished in 12 steps from the known cyclohexenol (±)-5.     

Highly diastereoselective synthesis of vicinal quaternary and tertiary stereocenters using the iodo-aldol cyclization

The intramolecular iodo-aldol cyclization of alpha-substituted enoate aldehydes and ketones is described. Using prochiral starting materials, the reaction produces hetero- and carbocycles containing quaternary centers adjacent to secondary or tertiary centers. The reactions occur in good yields and are highly selective for the trans-products, having the hydroxyl and iodomethyl groups on opposite faces of the ring system.     

Formation of chiral quaternary carbon stereocenters using silylene transfer reactions: enantioselective synthesis of (+)-5-epi-acetomycin

Chiral quaternary carbon stereocenters can be established with high diastereoselectivity by a silylene transfer/Ireland-Claisen rearrangement. The utility of this method was demonstrated by application to a synthesis of (+)-5-epi-acetomycin. [reaction: see text]     

Exploration of the enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters

Quaternary stereocenters on a 2-cyclohexen-1-one ring are synthesized with good to excellent levels of enantioselectivity. The quaternary stereocenter is created through a new synthetic sequence involving three reactions: the enantioselective Birch reduction-allylation, enol ether hydrolysis, and the Cope rearrangement. To illustrate the ability of the sequence to enantioselectively generate complex structures, a variety of substrates are described. Notably, the sequence works for the enantioselective generation of vicinal quaternary-tertiary stereocenters, the generation of congested arylic quaternary stereocenters, and hydroxyalkyl substituted quaternary stereocenters.     

Synthesis of manzacidin A and C: efficient construction of quaternary carbon stereocenters bearing nitrogen substituents

An efficient synthetic method for stereoselective construction of asymmetric quaternary carbon stereocenters, bearing nitrogen in the form of Boc-protected allyl amines, has been developed. This methodology is employed in the synthesis of marine alkaloids, manzacidin A and C.     

Manganese(III) acetate mediated oxidative radical cyclizations. Toward vicinal all-carbon quaternary stereocenters

Manganese(III) acetate mediated oxidative radical cyclizations have been used to synthesize a range of densely functionalized and sterically congested cyclopentane-lactones. A number of the resulting lactones contain vicinal all-carbon quaternary stereocenters adjacent to a tertiary benzylic stereocenter and are formed with high levels of stereocontrol.     

Highly diastereo- and enantioselective construction of phthalide-oxindole hybrids bearing vicinal quaternary chiral centers via an organocatalytic allylic alkylation

A diastereo- and enantioselective synthesis of phthalide-oxindole hybrids including congested adjacent quaternary chiral centers was demonstrated through a Lewis base catalyzed asymmetric allylic alkylation reaction of Morita–Baylis–Hillman carbonates of isatins and 3-cyanophthalides. The various hybrid molecules with two valuable pharmacophores-combined frameworks can be obtained in good to high diastereo- and enantioselectivities.