Manish Kumar

Synthesis of Chiral Ligands with Multiple Stereogenic Centers and Their Application in Titanium(IV)-Catalyzed Enantioselective Desymmetrization of meso-Epoxides

New chiral ligands, (S,R,S)‐1, (S,S,S)‐1, (S,S,R)‐1, (S,R,R)‐1, (R,R,R)‐1, (R,R,S)‐1, (R,S,S)‐1, (R,S,R)‐1, (S,R,S)‐2, (S,S)‐3 and (R,S)‐4 with diverse stereogenic centers arising from various diastereomeric combinations of aminoalcohol functionality with (R)‐ and (S)‐1,1‐binaphthol, were prepared and characterized. Catalytically active Ti complexes were generated inu2005situ in the presence of water for the enantioselective ring‐opening reaction of meso‐stilbene oxide, cyclohexene oxide, cyclopentene oxide, and cis‐butene oxide with different anilines as nucleophile. Significantly, catalysts Ti‐(S,R,S)‐1 and Ti‐(R,S,S)‐1 (15u2005molu2009%) produced syn‐beta‐amino alcohols of meso‐stilbene oxide with (1S,2S) and (1R,2R) configuration respectively in excellent yields (>98u2009%) and enantioselectivities (ee value >99u2009%) in 10u2005h at room temperature. However, aliphatic/cyclic epoxides with aniline gave better performance with the catalyst Ti‐(S,R,R)‐1. The complex Ti‐(S,R,S)‐1 was successfully subjected to catalyst recovery and recyclability experiments over 6 cycles in the asymmetric ring‐opening of meso‐stilbene oxide with aniline with retention of performance.

Enantioselective syntheses of β-amino alcohols catalyzed by recyclable chiral Fe(III) metal complex

An efficient asymmetric desymmetrization of meso-epoxides with anilines catalysed by a series of simple and environmentally benign in situ generated Fe(III) complexes based on chiral tridentate ligands L1–L7 with achiral and chiral linkers (methylene, piperazine, R/S BINOL and diethyl tartrate) was carried out at rt. The in situ generated iron metal complex based on ligand L5a emerged as improved (low catalyst loading) catalyst for asymmetric desymmetrization of meso-epoxides with anilines giving high enantioselectivity (up to 99%) and high yield (95%) of enantiopure β-amino alcohols in 14 h. While excellent results for ARO of cyclic as well as aliphatic epoxides with anilines was achieved with in situ generated complex from the ligand L4h and Fe(III) chloride, the catalyst was recoverable and recyclable (five times) with retention of its performance.

Enantioselective Desymmetrization of meso-Epoxides with Anilines Catalyzed by Polymeric and Monomeric Ti(IV) Salen Complexes

The active catalysts for the enantioselective ring opening (ARO) of meso-stilbene oxide, cis-butene oxide, cyclohexene oxide, cyclopentene oxide, and cyclooctene oxide with various substituted anilines were generated in situ by the reaction of Ti(O(i)Pr)(4) with poly-[(R,R)-N,N-bis-{3-(1,1-dimethylethyl)-5-methylene salicylidene} cyclohexane-1,2-diamine]-1 and (1R,2R)-N,N-bis[3,5-di(tert-butyl)salicylidene] cyclohexane-1,2-diamine-2. These catalysts in the presence of nonracemic imine as an additive provided β-amino alcohol in excellent yield (99%) and chiral purity (enantiomeric excess (ee) up to 99%) for the ARO of meso-stilbene oxide with aniline. The same protocol was less effective for the ARO of cyclic epoxides; however, when triphenylphosphine was used as an additive, there was a significant improvement in catalyst performance for the ARO of cyclohexene oxide (yield, 85-90%; ee, 63-67%). Both in situ generated polymeric and monomeric catalysts performed in a similar manner except that the polymeric catalyst Ti(IV)-1 was more active and recycled several times with retention of enantioselectivity when compared with the monomeric catalyst Ti(IV)-2, which was nonrecyclable.

Chiral Cu(II)-amino alcohol based complexes for asymmetric aza-Henry reaction of N-Ts imines

A series of chiral dimeric ligands 1A–C, 2A–B, 3A–B and 4A derived from (S)/(R) 1,1′-bi(2-naphthol)-bis-aldehyde/piperazine-bis-aldehyde and various aminoalcohols viz., (1R,2S)-(−)-2-aminodiphenylethanol, (1S,2R)-(−)-2-aminodiphenylethanol, (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol and (R)-valinol were synthesized. In situ generated complexes 1A–C–, 2A–B–, 3A–B–, 4A–Cu(II)/Cu(I) of dimeric chiral ligands with different copper salts were used as catalysts for the asymmetric aza-Henry reaction of a variety of N-tosylimines as substrates with different nitroalkanes at RT to afford good yields of aza-Henry products (80% with respect to the imines) with excellent enantioselectivity (ee > 99%) in 24 h with nitromethane and high syn selective products with excellent enantioselectivity with nitroethane. The dimeric chiral Cu(II) complex 1A–Cu(II) retained its performance at the gram level and was expediently recycled for a number of times. The enantio-pure aza-Henry product was further used for the synthesis of (S)-levamisole (an anthelminthic agent) in good yield and ee in three steps.

Asymmetric allylation of sulfonyl imines catalyzed by in situ generated Cu(II) complexes of chiral amino alcohol based Schiff bases

A catalytic route for enantioselective synthesis of homoallyl amines through Cu(II)-Schiff base catalyzed reaction of allyltin with aryl, alkenyl-substituted N-sulfonylimines is described. The allylation reaction is promoted by a simple in situ generated Cu(II)-amino alcohol based Schiff base complex. The addition of allyltin to aldimines delivers the desired products up to 90% yield and 98% enantiomeric excess (ee). Based on experimental observations a probable mechanism was proposed for this reaction. The current methodology was extended to the synthesis of β-phenylalanine in good yield and very good enantioselectivity.

Asymmetric hydrolytic kinetic resolution with recyclable polymeric Co(III)–salen complexes: a practical strategy in the preparation of (S)-metoprolol, (S)-toliprolol and (S)-alprenolol: computational rationale for enantioselectivity

A series of chiral polymeric Co(III)–salen complexes based on a number of achiral and chiral linkers were synthesized and their catalytic performances were assessed in the asymmetric hydrolytic kinetic resolution of terminal epoxides. The effects of the linker were judiciously studied and it was found that in the case of the chiral BINOL-based polymeric salen complex 1, there was an enrichment in catalyst reactivity and enantioselectivity of the unreacted epoxide, particularly in the case of short as well as long chain aliphatic epoxides. Good isolated yields of the unreacted epoxide (up to 46% compared to 50% theoretical yield) along with high enantioselectivity (up to 99%) were obtained in most cases using catalyst 1. Further studies showed that catalyst 1 could retain its catalytic activity for six cycles under the present reaction conditions without any significant loss in activity or enantioselectivity. To show the practical applicability of the above synthesized catalyst we have synthesised some potent chiral β-blockers in moderate yield and high enantioselectivity using complex 1. The DFT (M06-L/6-31+G**//ONIOM(B3LYP/6-31G*:STO-3G)) calculations revealed that the chiral BINOL linker influences the enantioselectivity achieved with Co(III)–salen complexes. Further, the transition state calculations show that the R-BINOL linker with the (S,S)-Co(III)–salen complex is energetically preferred over the corresponding S-BINOL linker with the (S,S)-Co(III)–salen complex for the HKR of 1,2-epoxyhexane. The role of non-covalent C–H⋯π interactions and steric effects has been discussed to control the HKR reaction of 1,2-epoxyhexane.

Development of recyclable chiral macrocyclic metal complexes for asymmetric aminolysis of epoxides: application for the synthesis of an enantiopure oxazolidine ring

New recyclable chiral salen complexes Cr(III)1–7 were synthesized from various macrocyclic chiral ligands having multistereogenic chiral centers which work synergistically to give the best results in terms of the enantioselectivity and yield of the products. Among the synthesized complexes, the Cr(III)-4 salen complex efficiently catalyzed the ring opening reaction of various aromatic ester epoxides, trans-epoxides and meso-epoxides with anilines to furnish the corresponding β-amino-α-hydroxyl esters and β-amino alcohols with an excellent ee of up to 99% and a high yield of up to 95%. Furthermore, the chirally pure β-amino-α-hydroxyl esters were converted into pharmaceutically important oxazolidine ring systems. Moreover, the chromium catalyst was recycled up to 5 cycles with the retention of its activity.