Asymmetric Mannich reactions with in situ generation of carbamate-protected imines by an organic catalyst

The instability of carbamate-protected alkyl imines has greatly hampered the development of catalytic asymmetric Mannich reactions suitable for the synthesis of optically active carbamate-protected chiral alkyl amines. A highly enantioselective Mannich reaction with in situ generation of carbamate-protected imines from stable alpha-amido sulfones catalyzed by an organic catalyst was developed. This reaction provides a concise and highly enantioselective route converting aromatic and aliphatic aldehydes into optically active aryl and alkyl beta-amino acids. [reaction: see text].     

Highly stereoselective synthesis of anti-N-protected-alpha-amino epoxides

A simple and efficient method for the synthesis of anti-N-protected amino epoxides from carbamate-protected amino acids is described. The two key steps are the monobromination of a beta-ketoester and chelation-controlled reduction of a bromomethyl ketone intermediate. Good overall yields, high diastereoselectivity, and excellent functional group compatibility are characteristic.     

trans-Cyclopropyl beta-amino acid derivatives via asymmetric cyclopropanation using a (Salen)Ru(II) catalyst

trans-Cyclopropyl beta-amino acid derivatives can be synthesized in five steps with excellent enantioselectivities using a chiral (Salen)Ru(II) cyclopropanation catalyst in the key asymmetry-induction step. This facile synthesis proceeds with high overall yield and can be used to prepare a number of carbamate-protected (Cbz and Boc are demonstrated) beta-amino acid derivatives.     

Copper-catalyzed N-arylation of carbamate-protected hydrazones with organobismuthanes

Efficient copper(II) acetate-catalyzed N-arylation of carbamate-protected hydrazones was achieved under mild reaction conditions with organobismuthanes.     

N-arylation of carbamate-protected glycine derivatives via palladium catalysis

A synthesis of N-aryl and N-heteroaryl amino acid derivatives using palladium catalysis is described. Several carbamate-protected glycine derivatives react with aryl and heteroaryl halides using a palladium/Xantphos catalyst system to access the desired synthons.     

Stereoselective rhodium-catalyzed amination of alkenes

The first stereoselective rhodium-catalyzed intermolecular aziridination and C-H amination of alkenes to produce chiral carbamate-protected aziridines and allylic amines is described. Good yields and diastereoselectivities were achieved using a readily available chiral N-tosyloxycarbamate and stoichiometric amount of the alkene substrate. Furthermore the protecting group is easy to cleave under mild reaction conditions.     

A general organic catalyst for asymmetric addition of stabilized nucleophiles to acyl imines

Cinchona alkaloid-derived thiourea catalysts promote nucleophilic additions to acyl imines for the asymmetric synthesis of secondary amine adducts. The hydroquinine-derived thiourea catalyst efficiently promotes the aza-Henry reaction of nitroalkane with acyl imines, affording β-nitroamines in good yields with enantioselectivities of 90-98% ee and diastereoselectivities up to 97%. The scope of the reaction also includes dimethyl malonate as a nucleophile to access β-amino esters in high enantiopurity. Under the optimized reaction conditions, secondary amine adducts of high enantiopurity are generated based on various aromatic and α,β-unsaturated acyl imines.     

Deconjugation of dehydroamino acids: stereoselective synthesis of racemic (E)-vinylglycines

[reaction: see text] A practical and general two-step synthesis of carbamate-protected (E)-vinylglycines from aliphatic aldehydes is reported. The key step involves the kinetic alpha-protonation of dianionic dienolates derived from dehydroamino acids.     

Catechol imine ligands: from helicates to supramolecular tetrahedra

Di- and tricatechol imines are easily accessible by condensation of appropriate amines with 2,3-dihydroxybenzaldehyde. Dicatechol imines can be used for the alkali metal template-directed self-assembly of dinuclear triple-stranded helicates or meso-helicates with high diastereoselectivity. Tricatechol imines lead in self-assembly processes to metallosupramolecular 4 [ratio] 4 tetrahedra with a huge internal cavity, which is able to encapsulate guest species. Hereby the special features of the imine unit can be used to control the outcome of the self-assembly process.     

Regioselectivity of rhodium nitrene insertion. Syntheses of protected glycals of l-daunosamine, d-saccharosamine, and l-ristosamine

[reaction: see text] The carbamate-protected glycals of naturally occurring 3,4-cis-3-amino-2,3,6-trideoxyhexoses (l-daunosamine, d-saccharosamine, and l-ristosamine) were prepared from noncarbohydrate starting materials. The short, high-yield syntheses are based on the chemoselective insertion of a rhodium nitrene in an allylic C-H bond rather than in a C-H bond that is alpha to an oxygen substituent.     

Asymmetric Friedel-crafts reaction of indoles with imines by an organic catalyst

In this communication, we report an asymmetric Friedel-Crafts reaction of indoles with imines catalyzed by a bifunctional cinchona alkaloid catalyst. This is the first efficient organocatalytic asymmetric Friedel-Crafts reaction of indoles with imines. This reaction is operationally simple and, unprecedentedly, affords high enantioselectivity for a wide range of indoles and both aryl and alkyl imines. This establishes a direct, convergent, and versatile approach to optically active 3-indolyl methanamines, a structural motif embedded in numerous indole alkaloids and synthetic indole derivatives.     

Synthesis of N-methylpyrrole and N-methylimidazole amino acids suitable for solid-phase synthesis

New and higher yielding synthetic routes to N-protected N-methylpyrrole and N-methylimidazole amino acids are introduced to circumvent difficulties associated with established schemes. Key steps in each synthesis include copper-mediated cross-coupling reaction to directly install a carbamate-protected 4-amine in the N-methylpyrrole derivative and effective nitration followed by a one-pot reduction/Boc protection of the amine in the synthesis of the N-Me-imidazole amino acid.     

Asymmetric phase-transfer-catalyzed conjugate addition of glycine imine to exocyclic α,β-unsaturated ketones: construction of polycyclic imines containing three stereocenters

We developed a facile, one-pot, multistep transformation between glycine imine and exocyclic α,β-unsaturated ketones in reactions catalyzed by chiral phase-transfer catalysts (PTC). A series of polycyclic imines containing three adjacent stereocenters were obtained in good to high yields with high diastereo- and enantioselectivities. Further transformation of the imines could afford N-fused polycyclic compounds with four adjacent stereocenters.     

Efficient kinetic resolution in the asymmetric hydrosilylation of imines of 3-substituted indanones and 4-substituted tetralones

Kinetic resolution of the N-methyl imines of 3-substituted indanones and 4-substituted tetralones could be accomplished by hydrosilylation with a chiral titanocene catalyst. N-Methyl imines of 4-substituted tetralones were resolved to yield, after hydrolysis of the unreacted starting materials, ketones with high ee's and the amine products with high diastereomeric and enantiomeric purity. The utility of this process was demonstrated in the synthesis of sertraline.     

Concise design and synthesis of pyridine-fused heterocycles via 6π-Azaelectrocyclization process of iminoalkyne derivatives

A concise and regioselective approach to the synthesis of pyridine-fused heterocycles and benzoxazepine derivatives was developed. Propargyl imines derived from aromatic aldehydes and propargyl amine underwent 6π-electrocyclization reactions at high temperatures in high yields to form pyridine-fused heterocycles. Application of the same methodology to aromatic imines having a hydroxyl group in the ortho position resulted in the formation of (benz)oxazepine derivatives. The formation mechanism of the products was discussed.     

Chemo- and regioselective assembly of polysubstituted pyridines and isoquinolines from isocyanides, arynes, and terminal alkynes

We have disclosed a general and efficient synthetic strategy for polysubstituted pyridines and isoquinolines with high chemo- and regioselectivity. In this methodology, 1-alkynyl imines act as the key compound to undergo a sequential alkynyl imine-allenyl imine isomerization/aza-Diels-Alder reaction/aromatization. In the first place, 1-alkynyl imines were formed in situ by a highly selective multicomponent reaction of isocyanides, arynes, and terminal alkynes and reacted with another molecule of arynes or terminal alkynes to furnish target heterocyclic products in a highly efficient and atom-economic manner. On the other hand, we attempted to prepare 1-alkynyl imines by other approaches to undergo a similar reaction sequence to afford polysubstituted pyridines and isoquinolines with a wider range. Different from the first approach, the second approach utilized the preprepared 1-alkynyl imines to introduce the related different substitutents into the final products: arynes or terminal alkynes bearing substituents different from those of 1-alkynyl imines have been successfully applied for the synthesis a wide variety of pyridines and isoquinolines with diversity.     

Synthesis of N6-phosphorylated sydnone imines and their functionalization via 4-Li derivatives. Novel bicyclic sydnone imines

The highly efficient gram-scale method for preparation of up to date hardly available N₆-phosphorylated sydnone imines based on the reaction of sydnone imine hydrochlorides with substituted phosphinate or phosphonate acids chlorides in the presence of a base was elaborated. A possibility of straight deprotonation of sydnone imines with n-BuLi followed by the reaction 4-Li-derivatives thus obtained with electrophiles was demonstrated. Novel representatives of bicyclic sydnone imines fused via 4,5-edge of the oxadiazolium ring were obtained. Also sydnone imines containing both phosphorus and sulfur functionalities were obtained with high yields.     

Phase-transfer-catalyzed alkylation of guanidines by alkyl halides under biphasic conditions: a convenient protocol for the synthesis of highly functionalized guanidines

An operationally straightforward and efficient method for the alkylation of carbamate-protected guanidines with various alkyl halides and mesylates is described. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine under biphasic conditions using a catalytic amount of a tetrabutylammonium salt as a phase-transfer catalyst. In this manner, highly functionalized guanidines can be obtained. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine component. In addition, the reaction is sufficiently mild such that simple aqueous workup and filtration through a short silica gel column yields the substituted guanidines in high purity. In conjunction with the EDCI-mediated guanylation of disubstituted thioureas with amines, phase-transfer catalyzed alkylation of guanidines via a one-pot, three-component synthesis of substituted guanidines was achieved.     

Lewis base-catalyzed additions of alkynes using trialkoxysilylalkynes

[reaction: see text]. The Lewis base-catalyzed additions of alkynyl nucleophiles to aldehydes, ketones, and imines is described. Mechanistic studies strongly indicate that the use of new triethoxysilylalkynes facilitates access of a reactive hypervalent silicate intermediate. This activated carbon nucleophile subsequently undergoes rapid addition to carbonyl compounds and imines, thus affording the secondary and tertiary propargyl systems in moderate to high yield.     

A synthesis of L-vancosamine derivatives from non-carbohydrate precursors by a short sequence based on the Marshall, McDonald, and Du Bois reactions

[reaction: see text] The carbamate-protected l-vancosamine glycal, viewed as a universal precursor for vancosamine derivatives, was prepared by a short scheme based on diastereoselective addition of an allenyl stannane to a lactaldehyde ether, the tungsten-catalyzed alkynol cycloisomerization, and the rhodium-catalyzed C-H insertion of a carbamate nitrogen. This sequence is a prototype for a new and efficient strategy for the synthesis of 3-amino sugar derivatives. The key intermediate was elaborated to the silyl ether of N,N-dimethyl vancosamine glycal.