Efficient synthesis of optically active atropisomeric anilides through catalytic asymmetric N-arylation reaction

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)2 catalyst, N-arylation of ortho-tert-butyl-NH-anilides with 4-nitroiodobenzene proceeds with high enantioselectivity (89-95% ee) to give optically active atropisomeric anilides possessing N-C chiral axis. Furthermore, the intramolecular version of the present catalytic asymmetric N-arylation gave atropisomeric lactams with high optical purity (94-96% ee).     

Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lactams having an N-C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.     

Catalytic enantioselective synthesis of key intermediates for NET inhibitors using atropisomeric lactam chemistry

An atropisomeric lactam which was prepared with high enantioselectivity by catalytic asymmetric intramolecular N-arylation, was efficiently converted to synthetic intermediates for NET inhibitors through highly diastereoselective α-alkylation followed by hydration and trans-tert-butylation.     

A new electronically deficient atropisomeric diphosphine ligand (S)-CF3O-BiPhep and its application in asymmetric hydrogenation

A new electronically deficient atropisomeric diphosphine ligand (S)-CF₃O-BiPhep was synthesized from 1-bromo-3-(trifluoromethoxy)benzene in high yield. The key steps included oxidative coupling with anhydrous ferric chloride and optical resolution by (+)-DMTA. The ligand afforded high performance for Ir-catalyzed asymmetric hydrogenation of quinolines with ee up to 92% and TON up to 25,000. It was also successfully applied to the Pd-catalyzed asymmetric hydrogenation of simple indoles with ee up to 87% and Rh-catalyzed asymmetric 1,4-addition of phenylboronic acid to 2-cyclohexenone with 97% ee.     

Efficient preparation of an N-aryl β-amino acid via asymmetric hydrogenation and direct asymmetric reductive amination en route to Ezetimibe

Two routes for the preparation of an N-aryl β-amino acid, an important precursor for the cholesterol-lowering drug Ezetimibe, were investigated. The first pathway proceeds via an Rh- or Ir-catalyzed asymmetric hydrogenation of N-aryl enamine giving the desired product with up to 82% ee. The other pathway involves a direct asymmetric reductive amination (DARA) of the β-keto ester which yielded the β-amino ester in high yield and 97% ee. Subsequent copper-catalyzed N-arylation gave the target compound.     

Nickel-catalyzed asymmetric alpha-arylation of ketone enolates

An atropisomeric dipyridyldiphosphine, P-Phos, can effect highly enantioselective Ni-catalyzed alpha-arylation of ketone enolates with aryl halides to install an all-carbon quaternary stereogenic center in up to 98% ee and excellent yields.     

Phase-transfer-catalyzed asymmetric glycolate alkylation

[reaction: see text] Asymmetric surrogate glycolate alkylation has been performed under phase-transfer conditions. Diphenylmethyloxy-2,5-dimethoxyacetophenone with trifluorobenzyl cinchonidinium catalyst and cesium hydroxide provided alkylation products at -35 degrees C in high yield (80-99%) and with excellent enantioselectivities (90:10 to 95:5). Useful alpha-hydroxy products were obtained using bis-TMS peroxide Baeyer-Villiger conditions and selective transesterification. The intermediate aryl ester can be obtained with >99% ee after a single recrystallization. A tight ion-pair model for the observed (S)-stereoinduction is proposed.     

A novel class of nonbiaryl atropisomeric P,O-ligands for palladium-catalyzed asymmetric allylic alkylation

[structure: see text]. A novel class of nonbiaryl atropisomeric P,O-ligands possessing an N,N-dialkyl-1-naphthamide skeleton has been synthesized via an efficient chemical resolution process. It represents the first example of axially chiral P,O-ligands devoid of central chirality. Up to 94.7% ee was obtained for the Pd-catalyzed asymmetric allylic alkylation (AAA). Effects of solvent, base, and the bulk of the C8 oxygen group of the P,O-ligand on the AAA reaction were examined.     

Organocatalytic asymmetric allylic alkylation of sulfonylimidates with Morita-Baylis-Hillman carbonates

The asymmetric allylic alkylation reaction of sulfonylimidates with various Morita-Baylis-Hillman (MBH) carbonates was accomplished by the catalysis of commercially available cinchona alkaloids catalyst (DHQD)2AQN.The corresponding allylic alkylation products were obtained in good yields with high stereoselectivities (up to 99% ee,89:11 dr).     

Biocatalytic asymmetric rearrangement of a methylene-interrupted bis-epoxide: simultaneous control of four asymmetric centers through a biomimetic reaction cascade

Asymmetric enzyme-catalyzed hydrolysis of methylene-interrupted bis-epoxides 1 a and 1 b catalyzed by bacterial epoxide hydrolases furnished tetrahydrofuran derivatives 2 a and 2 b through a hydrolysis-rearrangement cascade. Whereas racemic bis-oxiranes 1 b-d underwent kinetic resolution with moderate stereoselectivities to yield products with up to 92 % ee and 66 % de: meso-bis-oxirane cis,cis-1 a was transformed into (6R,7R,9S,10S)-2 a in 94 % ee and 89 % de at high conversion (85 %) by Rhodococcus sp. CBS 717.73 as the major product. The reaction sequence resembles a biomimetic reaction cascade and provides an efficient entry into the structural core of annonaceous acetogenins with simultaneous control of four stereocenters.     

SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of alpha-alkyl and beta-alkyl aldehydes

The proclivity of alpha-branched N-2'-benzyl-3'-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-, (S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated. The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving 2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-5,5-dimethyloxazolidin-2-ones to afford and array of alpha-substituted-N-acyl-5,5-dimethyloxazolidin- 2-ones (85-94% de) and subsequent reduction with DIBAL afforded directly non-racemic alpha-substituted aldehydes without loss of stereochemical integrity (87-94% ee). The extension of this protocol for the asymmetric synthesis of beta-substituted aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally > 95% de). Reduction of the conjugate addition products with DIBAL gives non-racemic beta-substituted aldehydes in high yields and in high ee (generally > 95% ee). This methodology is exemplified by the asymmetric synthesis of (R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.     

Direct asymmetric aldol reactions of acetone using bimetallic zinc catalysts

[reaction: see text] The enantioselective aldol reaction using a novel binuclear zinc catalyst of acetone with several aldehydes gave products in good yields (62-89%) with a high level of enantioselectivity (ee = 76-92%).     

Efficient amide-directed catalytic asymmetric hydroboration

A series of acyclic beta,gamma-unsaturated amides are shown to undergo highly regio- (>95%) and enantioselective (93-99% ee) rhodium-catalyzed hydroboration with pinacolborane (PinBH) using simple chiral monophosphite or phosphoramidite ligands in combination with Rh(nbd)2BF4. The most effective ligands identified are phosphoramidite 4, derived from BINOL and N-methylaniline, and phosphite 5c, prepared from the (4'-tert-butyl)phenyl TADDOL analogue and phenol. For example, (E)-3-hexenoic acid phenylamide ((E)-1) undergoes rhodium-catalyzed hydroboration with PinBH (0.5 mol % Rh(nbd)2BF4, 1.1 mol % BINOL-derived phosphoramidite 4, THF, 40 degrees C, 2 h) affording an intermediate boronate ester which after oxidation with basic hydrogen peroxide gives the beta-hydroxy amide, (S)-3-hydroxyhexanoic acid phenylamide ((S)-3), in good yield (80%) and high enantiomeric purity (99% ee). Isomeric disubstituted (E)- and (Z)-alkenes give nearly identical results, and a trisubstituted alkene substrate is also shown to undergo efficient hydroboration (97% ee). Moderate catalyst loading (0.5 mol %) and reaction temperatures in 25-40 degrees C range are generally effective. N-Phenyl amides are generally more efficient than the corresponding N-benzyl or N,N-dibenzyl analogues. Pinacolborane is found to be more efficient than catecholborane.     

Organocatalytic asymmetric aldol reaction in the presence of water

Water was found to be a suitable solvent for the l-prolinethioamide catalysed aldol reaction of various cyclic ketones with aromatic aldehydes. Treatment of 4-nitrobenzaldehyde with as little as 1.2 equiv. of cyclohexanone in the presence of the protonated catalyst 1-TFA, afforded aldol products in high yields (up to 97%) with high diastereo- and enantioselectivity (up to >5 : 95 dr and 98% ee). The use of a high excess of ketone was avoided by conducting the aldol addition in the presence of water. Furthermore, different 'salting-out' and 'salting-in' salts were investigated and it was proven that the rate of acceleration and the stereochemical outcome of the reaction are affected by hydrophobic aggregation. Scope and limitation studies revealed that electron deficient aldehydes afforded aldol products with high stereoselectivity in the presence of 1-Cl(2)CHCO(2)H. It was shown that various cyclic ketones, under the conditions found, gave aldol products with fair yields, even if they are used in substoichiometric amounts (1.2 to 2.0 equiv.).     

Mechanistic and stereochemical aspects of the asymmetric cyclocarbonylation of 1,6-enynes with rhodium catalysts

NMR and kinetic investigations of the cyclocarbonylation of 1,6-enynes with cationic rhodium(i) catalysts, modified with atropisomeric diphosphines, disprove the involvement of carbonyl species for 1,6-enyne activation; low-temperature catalysis, with molecular sieves as the carbon monoxide reservoir, is highly enantioselective (ee up to 97%).     

Atropisomeric amides as chiral ligands: using (-)-sparteine-directed enantioselective silylation to control the conformation of a stereogenic axis

An enantiomerically pure (1-trimethylsilyl)ethyl group, constructed by a (-)-sparteine-directed enantioselective quench of a laterally lithiated tertiary aromatic amide, exerts powerful thermodynamic control over the conformation of the adjacent tertiary amide substituent. Ortholithiation and functionalization of the amide in the 6-position allows the single amide conformer to be trapped as an enantiomerically and diastereoisomerically pure amide atropisomer. Protodesilylation of the amide gives functionalized atropisomeric amides with a stereogenic axis of single absolute configuration, whose barriers to racemization have been determined by polarimetry. Enantiomerically pure amides bearing phosphine substituents are effective ligands in a Pd-catalyzed allylic substitution reaction-the first use of a nonbiaryl atropisomer as a chiral ligand-and give products with 90% ee. The rate of racemization of the phosphine-substituted amide is powerfully influenced by the presence of palladium.     

Organocatalytic, asymmetric synthesis of 3-sulfenylated N-boc-protected oxindoles

Sulfenylated oxindoles: The first asymmetric sulfenylation of N-Boc-protected oxindoles has been developed to provide products containing a tetrasubstituted stereogenic center in high to excellent yields (86-98?%) and, in most cases, excellent enantioselectivities (up to 96?%?ee; see scheme).     

High performance of a chiral diene-rhodium catalyst for the asymmetric 1,4-addition of arylboroxines to alpha,beta-unsaturated ketones

[reaction: see text] A rhodium complex coordinated with (S,S)-2,5-dibenzylbicyclo[2.2.2]octa-2,5-diene (Bn-bod) showed high catalytic activity and high enantioselectivity in the asymmetric 1,4-addition of arylboroxines to cyclic alpha,beta-unsaturated ketones, 0.005-0.01 mol % of the catalyst giving high yields of the addition products with not lower than 94% ee. The turnover frequency of the catalyst is up to 1.4 x 10(4) h(-1).     

Ruthenium-catalyzed asymmetric hydrogenation of N-boc-indoles

Highly enantioselective hydrogenation of various N-Boc-indoles proceeded successfully in the presence of the ruthenium complex generated from an appropriate ruthenium precursor and a trans-chelate chiral bisphosphine PhTRAP. Various 2- or 3-substituted indoles were converted into chiral indolines with high enantiomeric excesses (up to 95% ee). The PhTRAP-ruthenium catalyst was able to promote the hydrogenation of 2,3-dimethylindoles, giving cis-2,3-dimethylindolines with 72% ee.     

Phase-transfer-catalyzed asymmetric acylimidazole alkylation

2-Acylimidazoles are alkylated under phase-transfer conditions with cinchonidinium catalysts at -40 degrees C with allyl and benzyl electrophiles in high yield with excellent enantioselectivity (79 to >99% ee). The acylimidazole substrates are made in three steps from bromoacetic acid via the N-acylmorpholine adduct. The catalyst is made in high purity allowing for S-product formation (6-20 h) under mild conditions, consistent with an ion-pair mechanism. The products are readily converted to useful ester products using methyltriflate and sodium methoxide, via a dimethylacylimidazolium intermediate without racemization. The process is efficient, direct, and amenable to other electrophiles and transformations that proceed through an enolate intermediate.