Chiral Γ-amino Alcohols Research Articles

Rhodium-Catalyzed Asymmetric Reductive Hydroformylation of α-Substituted Enamides.

Chiral γ-amino alcohols are prevalent structural motifs in natural products and bioactive compounds. Nevertheless, efficient and atom-economical synthetic methods toward enantiomerically enriched γ-amino alcohols are still lacking. In this study, a highly enantioselective rhodium-catalyzed reductive hydroformylation of readily available α-substituted enamides is developed, providing a series of pharmaceutically valuable chiral 1,3-amino alcohols in good yields and excellent enantioselectivities in a single step. The development of the 4,4'-bisarylamino-substituted BIBOP ligand is crucial for the success of this transformation. DFT calculations and experimental data have revealed the importance of hydrogen bonding between the N-H group in the structure of TFPNH-BIBOP and the enamide carbonyl group in promoting both high enantioselectivity and reactivity. This method has enabled the concise synthesis of several chiral pharmaceutical intermediates including a single-step synthesis of the key chiral intermediate of maraviroc.

Cu-Catalyzed Asymmetric Synthesis of γ-Amino Alcohols Featuring Tertiary Carbon Stereocenters.

Alkyne-functionalized oxetanes are presented as versatile substrates that in combination with amine reagents can be transformed into structurally diverse, chiral γ-amino alcohols featuring a tetrasubstituted tertiary stereocenter under Cu catalysis. Control experiments demonstrate the privileged nature of these oxetane precursors in terms of yield and asymmetric induction levels in the developed protocol, and postsynthetic modifications offer an easy way to access more advanced synthons.

Iridium-catalyzed enantioselective synthesis of chiral γ-amino alcohols and intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine

Chiral γ-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of β-amino ketones provides a straightforward and powerful tool for the synthesis of chiral γ-amino alcohols, but the asymmetric transformation is synthetically challenging. Here, a series of tridentate ferrocene-based phosphine ligands bearing modular and tunable unsymmetrical vicinal diamine scaffolds were designed, synthesized, and evaluated in the iridium-catalyzed asymmetric hydrogenation of β-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse β-tertiary-amino ketones and β-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral γ-amino alcohols with up to 99% yields, >99% ee values, and turnover number (TON) of 48,500. The gram-scale reactions with low catalyst loading showed the potential application in industrial synthesis of chiral drugs, such as (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.

Manganese-Catalyzed Asymmetric Formal Hydroamination of Allylic Alcohols: A Remarkable Macrocyclic Ligand Effect.

A unique family of chiral peraza N6 -macrocyclic ligands, which are conformationally rigid and have a tunable saddle-shaped cavity, is described. Utilizing their manganese(I) complexes, the first example of earth-abundant transition metal-catalyzed asymmetric formal anti-Markovnikov hydroamination of allylic alcohols was realized, providing a practical access to synthetically important chiral γ-amino alcohols in excellent yields and enantioselectivities (up to 99 % yield and 98 % ee). The single-crystal structure of a MnI complex indicates that the manganese atom coordinates with the chiral dialkylamine moiety in a bidentate fashion. Further DFT calculations revealed that five of the six nitrogen atoms in the ligand were engaged in multiple noncovalent interactions with Mn, an isopropanol molecule, and a β-amino ketone intermediate via coordination, hydrogen bonding, and/or CH⋅⋅⋅π interactions in the transition state, showing a remarkable role of the macrocyclic framework.

Anti‐Markovnikov Hydroamination of Racemic Allylic Alcohols to Access Chiral γ‐Amino Alcohols

A ruthenium-catalyzed formal anti-Markovnikov hydroamination of allylic alcohols for the synthesis of chiral γ-amino alcohols is presented. Proceeding via an asymmetric hydrogen-borrowing process, the catalysis allows racemic secondary allylic alcohols to react with various amines, affording enantiomerically enriched chiral γ-amino alcohols with broad substrate scope and excellent enantioselectivities (68 examples, up to >99 % ee).

A Selective Transformation of Enals into Chiral γ-Amino Alcohols

A one-pot synthesis of chiral amino alcohols from α,β-unsaturated aldehydes is reported which circumvents competitive 1,2- versus 1,4-boryl addition, by means of using a sterically hindered amine-derived imine. In addition to the complete chemoselectivity, modification of the Cu(I) catalyst with readily available chiral diphosphines, such as (R)-DM-BINAP, gave the 1,4-boryl addition products with high levels of asymmetric induction.

Enantioselective Ring Opening of Meso- and Racemic Epoxides with Phenyl Lithium Catalyzed by Chiral γ-Amino Alcohols Derived from α-D-Xylose

Enantioselective desymmetrization of symmetrical epoxides is one of the most attractive and useful methods to obtain optically active compounds, since the reaction can generate two contiguous stereogenic centers from an achiral starting material. A number of the asymmetric desymmetrization reaction by the ring opening of the epoxides with a wide variety of nitrogen, sulfur, oxygen, halogen, and cyano nucleophiles have been reported. However, only two examples have been reported for the ring opening reactions with carbon nucleophile, such as chiral schiff bases and salens-catalyzed reaction and stoichiometric chiral ligandmediated reaction by organolithiums. During the course of study on developing new chiral catalysts for the reaction, we found that chiral 1,2-O-isopropylidene-5-deoxy-5-dialkylamino-α-D-xylofuranones (1) (Figure 1) derived from α-Dxylose played a role as effective catalysts for such reaction. Herein we wish to report the results of the desymmetrization reaction using these catalysts. As a model system, the enantioselective ring opening reaction of cyclohexene oxide with phenyllithium was chosen. We initially investigated the efficacy of catalysts 1aj possessing different kinds of amine substituents at the 5position of the xylofuranose ring. The reaction was carried out by adding the epoxide to a mixture of 1.6 equiv. of phenyllithium and 0.05 equiv of 1 in hexane at room temperature, which provided (1R,2S)-2-phenylcyclohexanol with moderate to good chemical yields and enantioselectivities (Table 1). The enantioselectivity of product alcohol was determined by HPLC analysis using Chiralcel OD-H column. Of the catalysts examined, 1j afforded the best result to be found as 71% ee (entry 10, Table 1). Next, we examined the loading effect of the catalyst on enantioselectivity by varying only the amount of catalyst 1j for the same reaction. As shown in Table 2, the use of 5 mol% of 1j provided to be the best. Increasing the amount of 1j from 5 to 25 mol% did not significantly affect the enantioselectivity, which was 71% ee with 5 mol%, 71% ee with 10 mol% and 25 mol% (entries 1-4). The desymmetrization reactions for cyclpentene oxide and cis-2,3-epoxybutane, with PhLi using 5 mol% of 1j as the catalyst gave (1R,2S)-2-phenylcyclopentanol with 79% ee and (2R,3S)-3-phenyl-2-butanol with 54% ee (entries 5-6). Other symmetrical oxides, such as cis3,4-epoxy-1,4-dibenzyloxybutane and 3-phenyloxetane, did not undergo the ring opening reaction with PhLi under the

Synthesis of chiral norbornane derivatives as γ-amino alcohol catalysts: the effect of the functional group positions on the chirality transfer

Starting from (1 S,4 R) chiral ketone (+)- 6, we developed a synthetic route to the synthesis of new chiral γ-amino alcohols (+)- and (−)- syn-2-amino-7-hydroxy norbornane derivatives with excellent yields and enantiomeric excesses (up to 99%). These compounds were tested as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde presenting moderate results. The results obtained, compared with others previously reported, showed that the relative disposition of the amino and hydroxyl groups on C(2) and C(7) positions, play an important role in the catalytic activity.