Expedient synthesis of cyclopropane alpha-amino acids by the catalytic asymmetric cyclopropanation of alkenes using iodonium ylides derived from methyl nitroacetate

A highly enantioselective (up to 97.5% ee) and diastereoselective (95:5 dr trans/cis) Cu(I)-catalyzed cyclopropanation of alkenes using phenyliodonium ylide generated in situ from iodosobenzene and methyl nitroacetate is reported. The cyclopropanation took place with high enantioselectivity for a wide range of alkenes, and the reaction was performed at room temperature. 1-Nitrocyclopropyl esters are versatile building blocks to access the corresponding cyclopropane amino esters and aminocyclopropanes in two and three steps, respectively, from commercially available products.     

Cu-catalyzed asymmetric allylic alkylations of aromatic and aliphatic phosphates with alkylzinc reagents. An effective method for enantioselective synthesis of tertiary and quaternary carbons

Efficient enantioselective Cu-catalyzed allylic alkylations of aromatic and aliphatic allylic phosphates bearing di- and trisubstituted olefins are disclosed. Enantioselective C-C bond forming reactions are promoted in the presence of 10 mol % readily available chiral amino acid-based ligand (5 steps, 40% overall yield synthesis) and 5 mol % (CuOTf)2 x C6H6. Reactions deliver tertiary and quaternary stereogenic carbon centers regioselectively and in 78-96% ee. Data regarding the effect of variations in ligand structure on the efficiency and enantioselectivity of the alkylation process, as well as a mechanistic working model, are presented. The suggested model involves a dual role for the chiral Cu complex: association of the Cu(I) center to the olefin is facilitated by a two-point binding between the carbonyl of the ligand's amide terminus and the P=O of the substrate.     

Design of a small-molecule catalyst using intramolecular cation-pi interactions for enantioselective Diels-Alder and Mukaiyama-Michael reactions: L-DOPA-derived monopeptide.Cu(II) complex

[reaction: see text] We have designed a small-molecule artificial metalloenzyme that is prepared in situ from Cu(OTf)(2) or Cu(NTf(2))(2) (1.0 equiv) and l-DOPA-derived monopeptide (1.1 equiv). This catalyst (2-10 mol %) is highly effective for the enantioselective Diels-Alder (DA) and Mukaiyama-Michael (MM) reactions with alpha,beta-unsaturated 1-acyl-3,5-dimethylpyrazoles. The present results demonstrate that cation-pi interactions may be available for controlling the conformation of sidearms of chiral ligands, and monopeptides are readily tunable ligands that include only one chiral center.     

An asymmetric nitro-Mannich reaction applicable to alkyl, aryl, and heterocyclic imines

[reaction: see text] A protocol for the enantioselective nitro-Mannich coupling between alkyl, aryl, and heterocyclic p-methoxybenzylimines and trimethylsilylnitropropanate catalyzed by a chiral tBu-BOX Cu(II) catalyst is described. It uses the lowest reported loading of commercially available metal catalyst and chiral ligand, and gives the highest yields and selectivities for a broad substrate range including nonaromatic aldimines. The resultant beta-nitroamines are obtained in 70-94% enantiomeric excess in good yield and can be readily reduced to synthetically useful 1,2-diamines.     

Copper-catalyzed enantioselective substitution of allylic carbonates with diboron: an efficient route to optically active alpha-chiral allylboronates

A method for the synthesis of alpha-chiral allylboronates featuring the Cu(I)-catalyzed enantioselective substitution of readily available allylic carbonates with a diboron is described. Using this method, various alpha-chiral allylboronates, including functionalized allylboronates, were successfully synthesized, with high enantiomeric purity.     

A highly diastereo- and enantioselective copper(I)-catalyzed Henry reaction using a bis(sulfonamide)-diamine ligand

A series of bis(sulfonamide)-diamine (BSDA) ligands were synthesized from commercially available chiral α-amino alcohols and diamines. The chiral BSDA ligand 3a, coordinated with Cu(I), catalyzes the enantioselective Henry reaction with excellent enantioselectivity (up to 99%). Moreover, with the assistance of pyridine, a CuBr-3a system promotes the diastereoselective Henry reaction with various aldehyde substrates and gives the corresponding syn-selective adduct with up to a 99% yield and 32.3:1 syn/anti selectivity. The enantiomeric excess of the syn adduct was 97%.     

Exceptionally E‐ and β‐Selective NHC–Cu‐Catalyzed Proto‐Silyl Additions to Terminal Alkynes and Site‐ and Enantioselective Proto‐Boryl Additions to the Resulting Vinylsilanes: Synthesis of Enantiomerically Enriched Vicinal and Geminal Borosilanes

An exceptionally site‐ and E‐selective catalytic method for preparation of Si‐containing alkenes through protosilylation of terminal alkynes is presented. Furthermore, the vinylsilanes obtained are used as substrates to generate vicinal or geminal borosilanes by another catalytic process; such products are derived from enantioselective protoborations of the Si‐substituted alkenes. All transformations are catalyzed by N‐heterocyclic carbene (NHC) copper complexes. Specifically, a commercially available imidazolinium salt, cheap CuCl (1.0 mol %) and Me₂PhSi–B(pin), readily and inexpensively prepared in one vessel, are used to convert terminal alkynes to (E)‐β‐vinylsilanes efficiently (79–98 % yield) and in >98 % E and >98 % β‐selectivity. Vinylsilanes are converted to borosilanes with 5.0 mol % of a chiral NHC–Cu complex in 33–94 % yield and up to 98.5:1.5 enantiomeric ratio (e.r.). Alkyl‐substituted substrates afford vicinal borosilanes exclusively; aryl‐ and heteroaryl‐substituted alkenes deliver the geminal isomers preferentially. Different classes of chiral NHCs give rise to high enantioselectivities in the two sets of transformations: C₁‐symmetric monodentate Cu complexes are most suitable for reactions of alkyl‐containing vinylsilanes and bidentate sulfonate‐bridged variants furnish the highest e.r. for substrates with an aryl substituent. Working models that account for the observed trends in selectivity are provided. Utility is demonstrated through application towards a formal enantioselective total synthesis of naturally occurring antibacterial agent bruguierol A.     

Exploiting C3-symmetry in the dynamic coordination of a chiral trisoxazoline to copper(II): improved enantioselectivity, and catalyst stability in asymmetric lewis acid catalysis

Chiral C3-symmetric trisoxazolines are highly efficient stereodirecting ligands in enantioselective Cu(II) Lewis acid catalysis which is based on the concept of a stereoelectronic hemilability of the divalent copper; in direct comparison with the analogous bisoxazoline systems they are more efficient in the enantioselective alpha-amination as well as the enantioselective Mannich reaction of prochiral beta-ketoesters.     

Enantioselective Copper(I)‐Catalyzed Alkynylation of Oxocarbenium Ions to Set Diaryl Tetrasubstituted Stereocenters

An enantioselective, copper(I)‐catalyzed addition of terminal alkynes to isochroman ketals to set diaryl, tetrasubstituted stereocenters has been developed. The success of this reaction relies on identification of a Cu/PyBox catalyst capable of distinguishing the faces of the diaryl‐substituted oxocarbenium ion. This challenging transformation enables efficient conversion of readily available, racemic ketals into high‐value enantioenriched isochroman products with fully substituted stereogenic centers. High yields and enantiomeric excesses are observed for various isochroman ketals and an array of alkynes.     

Copper-Catalyzed Chemo- and Enantioselective Radical 1,2-Carbophosphonylation of Styrenes

The copper-catalyzed enantioselective radical difunctionalization of alkenes from readily available alkyl halides and organophosphorus reagents possessing a P−H bond provides an appealing approach for the synthesis of α-chiral alkyl phosphorus compounds. The major challenge arises from the easy generation of a P-centered radical from the P−H-type reagent and its facile addition to the terminal side of alkenes, leading to reverse chemoselectivity. We herein disclose a radical 1,2-carbophosphonylation of styrenes in a highly chemo- and enantioselective manner. The key to the success lies in not only the implementation of dialkyl phosphites with a strong bond dissociation energy to promote the desired chemoselectivity but also the utilization of an anionic chiral N,N,N-ligand to forge the chiral C(sp³)−P bond. The developed Cu/N,N,N-ligand catalyst has enriched our library of single-electron transfer catalysts in the enantioselective radical transformations.     

Cu(II)-catalyzed asymmetric hydrosilylation of diaryl- and aryl heteroaryl ketones: application in the enantioselective synthesis of orphenadrine and neobenodine

With certain amounts of sodium tert-butoxide and tert-butanol as additives, catalytic amounts of an inexpensive and easy-to-handle copper source Cu(OAc)(2)?H(2)O, a commercially available and air-stable non-racemic dipyridylphosphine ligand, as well as the stoichiometric desirable hydride donor polymethylhydrosiloxane (PMHS), formed a versatile in situ catalyst system for the enantioselective reduction of a broad spectrum of prochiral diaryl and aryl heteroarylketones in air, in high yields and with good to excellent enantioselectivities (up to 96?%). In particular, the practical viability of this process was evinced by its successful applications in the asymmetric synthesis of optically enriched potent antihistaminic drugs orphenadrine and neobenodine.     

Asymmetric conjugate addition reactions of Meldrum's acid derived acceptors employing chiral phosphoramidite ligands

[reaction: see text] The enantioselective conjugate addition reaction of Et(2)Zn to Meldrum's acid derived acceptors, mediated by a catalyst formed from Cu(O(2)CCF(3))(2) and a phosphoramidite ligand, is reported. Adducts are obtained in useful yields and up to 94% ee.     

Synergistic Cu/Pd Catalysis for Enantioselective Allylic Alkylation of Aldimine Esters: Access to α,α‐Disubstituted α‐Amino Acids

An unprecedented enantioselective allylic alkylation of readily available aldimine esters has been developed, and is catalyzed by a synergistic Cu/Pd catalyst system. This strategy provides facile access to nonproteinogenic α,α‐disubstituted α‐amino acids in high yield with excellent enantioselectivity. The more challenging double allylic alkylation of glycinate‐derived imine esters was also realized. Furthermore, this methodology was applied for the construction of the key intermediate of PLG peptidomimetics.     

2-alkenoyl pyridine N-oxides, highly efficient dienophiles for the enantioselective Cu(II)-bis(oxazoline) catalyzed Diels-Alder reaction

2-Alkenoyl pyridine N-oxides are introduced as a new kind of efficient dienophiles for the Cu(II)-bis(oxazoline) (BOX) catalyzed enantioselective Diels-Alder reaction affording higher reactivity and enantioselectivity (ee's up to 96%) than the corresponding nonoxidized 2-alkenoyl pyridines.     

Catalytic enantioselective addition of terminal 1,3-diynes to aromatic ketones: facile access to chiral nonracemic tertiary alcohols

An efficient, catalytic, and enantioselective 1,2-addition of terminal 1,3-diynes to aromatic ketones was realized in the presence of 10 mol% of a Cu(OTf)(2)-hydroxycamphor-sulfonamide complex, affording chiral tertiary alcohols in up to 94% yield and 90% ee.     

Chiral Cu(II) complex catalyzed enantioselective addition of phenylacetylene to N-aryl arylimines

Chiral tridentate N-tosylated aminoimine ligands were used in the Cu(II)-catalyzed enantioselective addition of phenylacetylene to N-aryl arylimines, affording products up to 92% ee.     

Enantioselective Copper‐Catalyzed Alkylation of Quinoline N‐Oxides with Vinylarenes

An asymmetric copper‐catalyzed alkylation of quinoline N ‐oxides with chiral Cu–alkyl species, generated by migratory insertion of a vinylarene into a chiral Cu−H complex, is reported. A variety of quinoline N ‐oxides and vinylarenes underwent this Cu‐catalyzed enantioselective alkylation reaction, affording the corresponding chiral alkylated N‐heteroarenes in high yield with high‐to‐excellent enantioselectivity. This enantioselective protocol represents the first general and practical approach to access a wide range of chiral alkylated quinolines.     

Enantioselective Total Synthesis of (−)‐Martinellic Acid

An enantioselective total synthesis of martinellic acid is described. The pyrroloquinoline alkaloid core is efficiently prepared from a quinoline, employing a method which relies on a newly developed Cu‐catalyzed enantioselective alkynylation using the chiral imidazole‐based biaryl P,N ligand StackPhos to establish the absolute stereochemistry. The remaining carbon atoms are then installed by means of a diastereoselective Pd‐catalyzed decarboxylative allylation and the synthesis is completed after straightforward functional‐group manipulation. This new synthetic method enables the most concise enantioselective synthesis of this important class of molecules to date.     

Enantioselective fluorination mediated by cinchona alkaloid derivatives/Selectfluor combinations: reaction scope and structural information for N-fluorocinchona alkaloids.

Cinchona-alkaloid/Selectfluor combinations efficiently fluorinate a variety of carbonyl compounds in a highly enantioselective manner to furnish chiral alpha-fluorocarbonyl compounds. The DHQB/Selectfluor combination is effective for the enantioselective fluorination of indanones and tetralones 1 in up to 91% ee. The first enantioselective syntheses of chiral derivatizing reagents 3 was accomplished with high ee and in high chemical yields by the DHQDA/Selectfluor combination. 3-Fluorooxindoles 7 were prepared with ee up to 83% using the (DHQ)2AQN/Selectfluor or the (DHQD)2PYR/Selectfluor combination. Since the combinations are conveniently prepared in situ from readily available reagents, the present system represents a practical method for enantioselective fluorination. X-ray crystallography and 1H NMR analyses of the cinchona alkaloids/Selectfluor combination have established that the species that mediate this novel reaction are N-fluoroammonium cinchona alkaloid tetrafluoroborates, which adopt open conformations.     

Enantioselective and stereodivergent hydromonofluoroalkylation of conjugated and remote dienes

Because of the widespread applications of optically active alkyl fluorides in medicinal and agro chemicals, enantioselective and even stereodivergent construction of alkyl fluorides remains highly desirable but underdeveloped. Transition-metal-catalyzed asymmetric hydrofluoroalkylation of readily available dienes represents a novel route to achieve this goal, yet receives scarce study. Here we report an intriguing palladium-catalyzed enantioselective hydromonofluoroalkylation reaction of conjugated dienes. Both monosubstituted and internal dienes proceed well with the transformation and furnish alkyl fluorides in generally >80% yield and >90% ee. A stereodivergent hydromonofluoroalkylation protocol via Pd/Cu co-catalysis is also established for the access to all four stereoisomers of corresponding moieties bearing a fully-substituted F-stereogenic center and vicinal tertiary carbon center. In addition, asymmetric migratory hydromonofluoroalkylation of skipped dienes is developed to realize the direct allylic CH fluoroalkylation. A compound library of enantioenriched cyclic fluorides is thus built to highlight the transformation potential of present methodology.