Organocatalytic asymmetric tandem Michael-Henry reactions: a highly stereoselective synthesis of multifunctionalized cyclohexanes with two quaternary stereocenters

A novel organocatalytic asymmetric tandem Michael-Henry reaction catalyzed by 9-amino-9-deoxyepiquinine (VI) has been developed. The reaction was efficiently catalyzed by catalyst VI to give highly functionalized cyclohexanes with four stereogenic carbons including two quaternary stereocenters in excellent enantioselectivities (97 to >99% ee) and high diastereoselectivities (93:7-99:1 dr). Thus, the first organocatalytic asymmetric Henry reaction of common ketones as acceptors is shown.     

Organocatalytic asymmetric synthesis of 3(2H)-furanones with adjacent quaternary and tertiary stereocenters

An efficient stereoselective Michael addition of simple 3(2H)-furanones to α,β-unsaturated ketones has been described. The protocol provides a facile and efficient access to complex 3(2H)-furanones containing adjacent quaternary and tertiary stereocenters in high yields (up to 99%) with good diastereoselectivities (up to 86:14) and excellent enantioselectivities (up to 98% ee) under mild conditions.     

Catalytic enantioselective construction of vicinal quaternary carbon stereocenters

This review summarizes the advances in the catalytic enantioselective construction of vicinal quaternary carbon stereocenters, introduces major synthetic strategies and discusses their advantages and limitations, highlights the application of known protocols in the total synthesis of natural products, and outlines the synthetic opportunities.

This review summarizes the advances in catalytic enantioselective construction of vicinal quaternary carbon stereocenters, introduces major synthetic strategies and discusses their advantages and limitations, and outlines the synthetic opportunities.     

Rhodium-catalyzed asymmetric construction of quaternary carbon stereocenters: ligand-dependent regiocontrol in the 1,4-addition to substituted maleimides

A rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to substituted maleimides has been described. The regioselectivity in this reaction is controlled by the choice of ligand (dienes or bisphosphines), and 1,4-adducts with a quaternary stereocenter can be obtained with high regio- and enantioselectivity by the use of (R)-H8-binap.     

Enantioselective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction

A new electron-deficient chiral triazolium salt has been shown to catalyze the formation of quaternary stereocenters by an asymmetric intramolecular Stetter reaction. Pentafluorophenyl substitution on an aminoindanol-derived catalyst affords tertiary ether, thioether, and quaternary stereocenters in typically greater than 90% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction. The reaction proceeds at room temperature under mild conditions to provide quaternary stereocenters with functional group relationships that are particularly difficult to access by other methods.     

Cu(I)-catalyzed decarboxylative aldol-type and Mannich-type reactions for asymmetric construction of contiguous trisubstituted and quaternary stereocenters

The catalytic asymmetric decarboxylative aldol-type reaction between aldehydes and cyanocarboxylic acids and Mannich-type reaction between aldimines and cyanocarboxylic acids were developed. α,α,β-Trisubstituted-β-hydroxy nitriles bearing contiguous all-carbon quaternary and trisubstituted stereocenters were produced with moderate enantio- and diastereoselectivity in the presence of 10 mol % CuOAc–TANIAPHOS (or DTBM-SEGPHOS) complex in the aldol-type reaction. α,α,β-Trisubstituted-β-amino nitriles containing contiguous all-carbon quaternary and trisubstituted stereocenters were produced with moderate to high enantio- and diastereoselectivity using 5 mol % CuOAc–(R)-DTBM-SEGPHOS complex in the Mannich-type reaction. These reactions proceed through Cu(I)-catalyzed decarboxylative nucleophile generation, followed by the addition of the resulting chiral Cu-ketenimide to aldehydes or imines. Because the reactions proceed under very mild conditions at nearly neutral pH, the reactions are applicable to a wide range of substrate combinations, including both aromatic and aliphatic substrates. Finally, α,α,β-trisubstituted-β-amino nitriles were converted to β^2,2,3-amino acid derivatives through simple acidic hydrolysis without any racemization and epimerization.     

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.     

New auxiliaries for copper-catalyzed asymmetric Michael reactions: generation of quaternary stereocenters at room temperature

Dialkyl amides of L-valine, L-isoleucine, and L-tert-leucine (2) are excellent chiral auxiliaries for the construction of quaternary stereocenters at ambient temperature. Enaminoesters 3, prepared from these auxiliaries 2 and Michael donors 1, undergo a copper-catalyzed asymmetric Michael reaction with methyl vinyl ketone (MVK, 4) to afford products 5 in 70-90% yield and 90-99% ee (enantiomeric excess). The exclusion of moisture or oxygen is not necessary. The auxiliaries 2 are readily available by standard procedures. After workup they can be recovered almost quantitatively.     

Asymmetric construction of all-carbon quaternary stereocenters in the total synthesis of natural products

Structure units containing all-carbon quaternary stereogenic center are found in many bioactive natural products. However, enantioselective construction of this type of structure units has been a formidable challenge for synthetic community due to the steric hindrance enforced by all-carbon quaternary stereocenters. In this review, we present the achievements made by Chinese scientists in the area of asymmetric synthesis of all-carbon quaternary stereocenters in natural products during the past two years.     

Organocatalytic enantioselective multicomponent cascade reaction: facile access to tetrahydropyridines with C3 all-carbon quaternary stereocenters

A novel organocatalytic asymmetric multicomponent cascade reaction for the synthesis of valuable tetrahydropyridines has been developed. The merit of this cascade process is highlighted by its high efficiency of producing five new bonds and an all-carbon quaternary stereocenter in one operation, which otherwise is a big challenge to access by traditional strategies.     

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.     

Generation of quaternary stereocenters by asymmetric Michael reactions: enamine regiochemistry as configuration switch

Regioselective enamine formation from cyclic β‐diketones 1 is obtained by the appropriate choice of activating agent: Brønsted acid catalyzed condensation gives endocyclic enamines 3 as the thermodynamically favored products. Activation with Lewis acid BF₃ ? OEt₂ affords betaines 8 as intermediate products, which can be reacted with L ‐valine diethylamide ( 2 ) to preferentially furnish exocyclic enamines 4 as kinetic products. Derivatives with quaternary stereocenters were accessible from both isomeric enamines by using asymmetric, copper(II )‐catalyzed Michael reactions at ambient temperature. Both regioisomers afford the triketones 7 with the same constitution but bearing the opposite absolute configuration at the quaternary stereocenter. Thus, both enantiomers of the product are prepared by using the same chiral auxiliary derived from L ‐valine.     

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.     

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.     

Organocatalytic asymmetric destruction of 1-benzylated Reissert compounds catalysed by quaternary cinchona alkaloids

The enantiomeric enrichment of racemic 1-benzylated Reissert compounds under organocatalytic biphasic conditions is presented. The enrichment is the consequence of an asymmetric destruction of the racemic compounds resulting in the formation of the corresponding 1-benzylated isoquinolines. The highest selectivity has been achieved using quaternary cinchona alkaloids as phase-transfer catalysts. The resolution of a number of racemic 1-benzylated Reissert compounds reveals a significant substrate dependence and a proposal for the mechanism of the reaction is presented.     

Asymmetric construction of quaternary stereocenters by direct conjugate addition of oxindoles to enone

Chiral cinchona-based primary amine A was found to catalyze the asymmetric direct conjugate addition of prochiral 3-oxindoles with enones to afford 3,3-disubstituted oxindoles in good yields, moderate to high diastereoselectivities, and excellent enantioselectivities.     

Highly enantioselective construction of CF3-bearing all-carbon quaternary stereocenters: Chiral spiro-fused bisoxazoline ligands with 1,1'-binaphthyl sidearm for asymmetric Michael-type Friedel-Crafts reaction

A novel class of chiral spiro-fused bisoxazoline ligands possessing a deep chiral pocket was prepared.The developed ligands have been employed in the nickel-catalyzed highly enantioselective Michael-type Friedel-Crafts reaction, affording the products bearing a trifluoromethylated all-carbon quaternary stereocenter with moderate to excellent yields（up to 99%） and good to excellent enantioselectivies（up to> 99.9% ee）. Moreover, a proposed model of chiral pocket revealed that the attack of indo...     

Quinine-catalyzed asymmetric domino Michael-cyclization reaction for the synthesis of spirocyclic oxindoles bearing two spiro quaternary centers and three consecutive stereocenters

An efficient organocatalytic diastereo- and enantioselective method for the construction of spirocyclic oxindole derivatives bearing two spiro quaternary centers and three consecutive stereocenters via a domino Michael/cyclization process has been developed. Using commercially available quinine as catalyst, the reactions of 3-isothiocyanato oxindoles with unsaturated pyrazolones and unsaturated isoxazolones proceeded smoothly under mild reaction conditions for giving two classes of spirocyclic oxindole compounds in high to excellent yields with moderate to good diastereoselectivities and enantioselectivities. A plausible dual activation working model was tentatively proposed to account for the stereochemistry of the domino Michael/cyclization process.     

Diastereoselective indium-mediated allylation of N-tert-butanesulfinyl ketimines: easy access to asymmetric quaternary stereocenters bearing nitrogen atoms

Indium-mediated allylation of N-tert-butanesulfinyl ketimines afforded in high yields and diastereoselectivities homoallylic amine derivatives with the nitrogen atom bonded to a quaternary stereocenter.