Rh-catalyzed asymmetric hydrogenation of gamma-phthalimido-substituted alpha,beta-unsaturated carboxylic acid esters: an efficient enantioselective synthesis of beta-aryl-gamma-amino acids

A series of chiral beta-aryl-gamma-amino acid ester derivatives were synthesized in high enantioselectivities (93-97% ee) via the Rh-catalyzed asymmetric hydrogenation of gamma-phthalimido-alpha,beta-unsaturated carboxylic acid esters using highly modular chiral BoPhoz-type phosphine-aminophosphine ligands. The method has been applied successfully to the synthesis of several chiral pharmaceuticals including (R)-baclofen and (R)-rolipram with high enantioselectivities.     

Asymmetric 1,4-hydrosilylations of alpha,beta-unsaturated esters

Complexing catalytic amounts of CuH with a nonracemic JOSIPHOS or SEGPHOS ligand, together with stoichiometric PMHS, leads to exceedingly efficient and highly enantioselective 1,4-reductions of beta,beta-disubstituted enoates and lactones. An unprecedented substrate-to-ligand ratio of 7700:1 for this type of reaction is documented.     

Highly regio- and stereoselective asymmetric bromoazidation of chiral alpha,beta-unsaturated carboxylic acid derivatives: scope and limitations

Lewis acid catalyzed asymmetric bromoazidation of chiral alpha,beta-unsaturated carboxylic acid derivatives was performed using N-bromosuccinimide (NBS) and trimethylsilyl azide (TMSN3) as the bromine and azide sources. Among the Lewis acids, Yb(OTf)3 was found to be the best catalyst. Regio- and anti-selectivity of 100% and moderate to good diastereoselectivity (up to 89:11) with good yields were obtained when Oppolzer's bornane sultam chiral auxilairy was used. Diastereoselectivity of >95:05 was observed when (2S,5S)-2,5-diphenylpyrrolidine was used as the chiral auxiliary.     

Calcium-catalyzed diastereo- and enantioselective 1,4-addition of glycine derivatives to alpha,beta-unsaturated esters

The first highly diastereo- and enantioselective catalytic asymmetric 1,4-addition reactions of a glycine Schiff base to beta-substituted alpha,beta-unsaturated esters have been developed. The reaction pathway was successfully controlled, and the desired 1,4-addition products were exclusively obtained with high enantioselectivities. The product obtained was converted to a 3-substituted glutamic acid derivative by acid hydrolysis.     

Catalytic asymmetric epoxidation of alpha,beta-unsaturated esters using an yttrium-biphenyldiol complex

We succeeded in a catalytic asymmetric epoxidation reaction of alpha,beta-unsaturated esters via a conjugate addition of an oxidant using 2-10 mol % of the yttirium-chiral biphenyldiol catalyst. A variety of substrates with beta-aryl and beta-alkyl substituents were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy esters in up to 97% yield and 99% ee.     

Catalytic asymmetric 1,4-addition reactions using alpha,beta-unsaturated N-acylpyrroles as highly reactive monodentate alpha,beta-unsaturated ester surrogates

Synthesis and application of alpha,beta-unsaturated N-acylpyrroles as highly reactive, monodentate ester surrogates in the catalytic asymmetric epoxidation and Michael reactions are described. alpha,beta-Unsaturated N-acylpyrroles with various functional groups were synthesized by the Wittig reaction using ylide 2. A Sm(O-i-Pr)(3)/H(8)-BINOL complex was the most effective catalyst for the epoxidation to afford pyrrolyl epoxides in up to 100% yield and >99% ee. Catalyst loading was successfully reduced to as little as 0.02 mol % (substrate/catalyst = 5000). The high turnover frequency and high volumetric productivity of the present reaction are also noteworthy. In addition, a sequential Wittig olefination-catalytic asymmetric epoxidation reaction was developed, providing efficient one-pot access to optically active epoxides from various aldehydes in high yield and ee (96-->99%). In a direct catalytic asymmetric Michael reaction of hydroxyketone promoted by the Et(2)Zn/linked-BINOL complex, Michael adducts were obtained in good yield (74-97%), dr (69/31-95/5), and ee (73-95%). This represents the first direct catalytic asymmetric Michael reaction of unmodified ketone to an alpha,beta-unsaturated carboxylic acid derivative. The properties of alpha,beta-unsaturated N-acylpyrrole are also discussed. Finally, the utility of the N-acylpyrrole unit for further transformations is demonstrated.     

Asymmetric synthesis of carboxylic acid derivatives having an all-carbon alpha-quaternary center through Cu-catalyzed 1,4-addition of dialkylzinc reagents to 2-aryl acetate derivatives

The asymmetric synthesis of carboxylic acid derivatives having an all-carbon alpha-quaternary center has been achieved via copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives in the presence of phosphoramidite ligand. High isolated yields and enantioselectivities were obtained. It was demonstrated that the Meldrum's acid and ester moieties present on the all-carbon quaternary center allow for a wide variety of subsequent transformations, leading to the expedient preparation of succinimides, succinate esters and succinic acids, gamma-butyrolactones, and beta-amino acid derivatives.     

Enantioselective construction of stereogenic quaternary centres via Rh-catalyzed asymmetric addition of alkenylboronic acids to alpha,beta-unsaturated pyridylsulfones

The highly enantioselective construction of all-carbon quaternary stereogenic centres via Rh-catalyzed Chiraphos-mediated conjugate addition of alkenylboronic acids to beta,beta-disubstituted alpha,beta-unsaturated 2-pyridylsulfones is described.     

New synthesis of 1,4-diketones via rhodium-catalysed 1,4 carbonylative addition of arylboronic acids to alpha,beta-unsaturated ketones

The reaction of various arylboronic acids with alpha,beta-unsaturated ketones under CO pressure and in the presence of rhodium catalyst yields 1,4-diketones.     

Synthesis of alpha,beta-unsaturated gamma-lactams via asymmetric iridium-catalysed allylic substitution

Syntheses of alpha,beta-unsaturated gamma-lactams are described that are based on ring-closing metathesis in combination with enantioselective Ir-catalysed allylic amination using N-Boc-N-(but-2-enoyl)-amine as a pronucleophile. As an example application, the synthesis of a Baclofen analogue is presented.     

On the mechanism of an asymmetric alpha,beta-unsaturated carboxylic acid hydrogenation: application to the synthesis of a PGD2 receptor antagonist

Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of alpha,beta-unsaturated ene acid 1-E to give 2, a prostaglandin D2 (PGD2) receptor antagonist. With [(S-BINAP)Ru(p-cymene)Cl2]2 (3, S-BINAP = (S)-(+)-2,2'-bis(diphenylphospino)-1,1'-binapthyl), it was discovered that low hydrogen pressures (<30 psi) were essential to achieve high enantioselectivities (92% ee). A detailed mechanistic study was undertaken to elucidate this pressure dependence. It was determined that compound 1-E is in a ruthenium-catalyzed equilibrium with endocylic isomer 1-Endo and in photochemical equilibrium with Z isomer 1-Z. Each isomer could be hydrogenated to give 2, albeit with different rates and enantioselectivities. Hydrogenation of 1-Endo with 3 was found to give 2 in high enantiomeric excess, regardless of pressure and at a rate substantially faster than that of hydrogenation of 1-E and 1-Z. In contrast, isomers 1-E and 1-Z exhibited pressure-dependent enantioselectivities, with higher enantiomeric excesses obtained at lower pressures. A rationale for this pressure dependence is described. Deuterium labeling studies with 1-Endo and tiglic acid were used to elucidate the mechanism of hydride insertion and product release from ruthenium. Under neutral conditions, protonolysis was the major pathway for metal-carbon cleavage, while under basic conditions, hydrogenolysis of the metal-carbon bond was predominant.     

Enantioselective synthesis of branched allylic esters via rhodium-catalyzed coupling of allenes with carboxylic acids

We report on the first intermolecular asymmetric catalytic regio- and enantioselective addition of carboxylic acids to terminal allenes to form valuable branched allylic esters, employing a rhodium(I)/(R,R)-DIOP catalyst system.     

Enantioselective synthesis of chiral sulfones by Rh-catalyzed asymmetric addition of boronic acids to alpha,beta-unsaturated 2-pyridyl sulfones

A general and efficient method for the rhodium-catalyzed enantioselective catalytic conjugate addition of organoboronic acids to alpha,beta-unsaturated sulfones is described. The success of the process relies on the use of alpha,beta-unsaturated 2-pyridyl sulfones as key metal-coordinating substrates; typical sulfones such as vinyl phenyl sulfones are inert under the reaction conditions. Among a variety of chiral ligands, Chiraphos provided the best asymmetric induction. This rhodium [Rh(acac)(C2H4)2]/Chiraphos catalyst system has a broad scope, being applicable to the addition of both aryl and alkenyl boronic acids to cis and trans alpha,beta-unsaturated 2-pyridyl sulfones. In most cases, especially in the addition of aryl boronic acids, the reactions take place cleanly and with high enantioselectivity, affording chiral beta-substituted 2-pyridyl sulfones in good yields and enantioselectivities (70-92% ee). The sense and magnitude of this enantioselectivity have been studied by DFT theoretical calculations of the aryl-rhodium insertion step. These calculations strongly support the formation of a five-membered pyridyl-rhodium chelated species as the most stable complex after the insertion into the C=C bond. These highly enantioenriched chiral sulfones are very appealing building blocks in enantioselective synthesis. For instance, the straightforward elimination of the 2-pyridylsulfonyl group by either Julia-Kociensky olefination or alkylation/desulfonylation sequences provides a variety of functionalized chiral compounds, such as allylic substituted alkenes or beta-substituted ketones and esters.     

On the synthesis of Z-gamma-amino-alpha,beta-unsaturated esters via Ru-catalyzed coupling

[formula: see text] A synthesis of gamma-amino acids and their cyclic derivatives, 3-pyrrolinones, from alpha-amino acids employs a ruthenium-catalyzed Alder ene reaction as a key step in the sequence. Cyclopentadienylruthenium (1,4-cyclooctadiene) chloride catalyzes the addition of gamma-amido-alpha,beta-alkynoate esters with monosubstituted alkenes. The major product arises from C-C bond formation at the alpha-carbon of the alkynoate. The reaction exhibits high chemoselectivity. The ruthenium-catalyzed addition occurs in preference to a Diels-Alder reaction. The two new double bonds are created with complete geometrical control. The initial gamma-amido-alpha,beta-unsaturated ester can be cyclized to the pyrrolinones with a tin catalyst.     

Copper-catalyzed asymmetric conjugate addition of diethylzinc to alpha,beta-unsaturated imines derived from alpha-aminoacids. Enantioselective synthesis of gamma-substituted alpha-dehydroaminoesters

[Structure: see text] A highly enantioselective synthesis of alpha-dehydroaminoacids with a stereogenic center in the gamma position through copper-catalyzed asymmetric conjugate addition of diethylzinc to alpha,beta-unsaturated imines using a TADDOL-derived phosphoramidite complex is reported.     

Cu-catalyzed one-pot multicomponent approach for the synthesis of symmetric and asymmetric 1,4-dihydropyridine (1,4-DHP) linked 1,2,3-triazole derivatives

Abstract

Synthesis of various symmetric and asymmetric 1,4-DHP linked 1,2,3-triazole derivatives from economical and readily available starting materials via a convenient methodology in a single-pot method using CuSO₄·5H₂O as an efficient catalyst has been reported. The reaction proceeded efficiently under the optimized reaction conditions with excellent functional group compatibility providing the desired products in good yields. The method appears to be an efficient combinatorial strategy for the synthesis of new 1,4-DHP linked triazole derivatives.