Arghya Sadhukhan

C2-Symmetric Recyclable Organocatalyst for Enantioselective Strecker Reaction for the Synthesis of α-Amino Acid and Chiral Diamine- an Intermediate for APN Inhibitor

Recyclable chiral amide-based organocatalyst 5 efficiently catalyzed asymmetric Strecker reaction of various aromatic and aliphatic N-benzhydrylimines with ethyl cyanoformate as cyanide source at -10 °C to give a high yield (95%) of α-aminonitriles with excellent chiral induction (ee, up to 99%) with the added advantage of recyclability. Based on experimental observations a probable mechanism was proposed for this reaction. This protocol with catalyst 5 was extended for the synthesis of (R)-phenylalanine and pharmaceutically important drug intermediate (R)-3-phenylpropane-1,2-diamine in high yield with high enantioselectivity.

Asymmetric Hydrolytic Kinetic Resolution with Recyclable Macrocyclic CoIII–Salen Complexes: A Practical Strategy in the Preparation of (R)-Mexiletine and (S)-Propranolol

A chiral cobalt(III) complex (1e) was synthesized by the interaction of cobalt(II) acetate and ferrocenium hexafluorophosphate with a chiral dinuclear macrocyclic salen ligand that was derived from 1R,2R-(-)-1,2-diaminocyclohexane with trigol bis-aldehyde. A variety of epoxides and glycidyl ethers were suitable substrates for the reaction with water in the presence of chiral macrocyclic salen complex 1e at room temperature to afford chiral epoxides and diols by hydrolytic kinetic resolution (HKR). Excellent yields (47% with respect to the epoxides, 53% with respect to the diols) and high enantioselectivity (ee>99% for the epoxides, up to 96% for the diols) were achieved in 2.5-16 h. The Co(III) macrocyclic salen complex (1e) maintained its performance on a multigram scale and was expediently recycled a number of times. We further extended our study of chiral epoxides that were synthesized by using HKR to the synthesis of chiral drug molecules (R)-mexiletine and (S)-propranolol.

Modified Asymmetric Strecker Reaction of Aldehyde with Secondary Amine: A Protocol for the Synthesis of S-Clopidogrel (An Antiplatelet Agent)

A first approach for catalytic asymmetric Strecker reaction of aldehydes with a secondary amine in the presence of sodium fluoride using hydroquinine as chiral catalyst was developed. The catalytic system gave α-aminonitriles in excellent yields (up to 95%) and high enantioselectivities (er up to 94:6). The efficacy of the chiral product was successfully fulfilled in the improved synthesis of (S)-clopidogrel (an antiplatelet agent).

Oxazoline‐Based Organocatalyst for Enantioselective Strecker Reactions: A Protocol for the Synthesis of Levamisole

A chiral oxazoline-based organocatalyst has been found to efficiently catalyze asymmetric Strecker reactions of various aromatic and aliphatic N-benzhydrylimines with trimethylsilyl cyanide (TMSCN) as a cyanide source at -20 °C to give α-aminonitriles in high yield (96 %) with excellent chiral induction (up to 98 % ee). DFT calculations have been performed to rationalize the enantioselective formation of the product with the organocatalyst in these reactions. The organocatalyst has been characterized by single-crystal X-ray diffraction analysis, as well as by other analytical methods. This protocol has been extended to the synthesis of the pharmaceutically important drug molecule levamisole in high yield and with high enantioselectivity.

Asymmetric Hydrocyanation of Nitroolefins Catalyzed by an Aluminum(III) Salen Complex

Chiral AlIII salen complexes were synthesized and used as catalysts for the asymmetric hydrocyanation of nitroolefins using 4‐phenylpyridine N‐oxide as an additive and trimethylsilyl cyanide (TMSCN) as a source of cyanide. An excellent yield of β‐nitronitrile (87 %) and enantioselectivity (90 %) were achieved if (2‐nitrovinyl)cyclohexane was used as a substrate at −15 °C in 16 h. To understand the interaction of the AlIII salen complex and additive, NMR and IR spectroscopic studies revealed that 4‐phenylpyridine N‐oxide acts both as an axial ligand and helps to activate the cyanide source TMSCN, which thereby increases the reactivity. A catalytic cycle was proposed based on the spectroscopic studies.

Asymmetric Cyanoethoxy Carbonylation Reaction of Aldehydes Catalyzed by a TiIV Macrocyclic Complex: An Efficient Synthetic Protocol for β-Blocker and α1-Adrenergic Receptor Agonists

Chiral macrocyclic TiIV–salen complexes were used as efficient catalysts in the asymmetric cyanoethoxy carbonylation of aldehydes. The TiIV catalysts demonstrated excellent performance (product yields and ee values up to 99 %) with ethyl cyanoformate as the cyanide source and a catalyst loading of 0.5 mol %, which is the lowest known. The macrocyclic TiIV–salen complex retained its performance at multigram level and was conveniently recycled for a number of times. The product obtained was straightforwardly transformed to the pharmaceutically important chiral drugs (R)‐proethalol (β‐blocker) and (R)‐phenylephrine (α1‐adrenergic receptor agonist) in good yields. To understand the mechanism of the catalytic reaction, a kinetic investigation was conducted with various concentrations of the catalyst, ethyl cyanoformate and benzaldehyde as the representative substrate. The reaction of benzaldehyde was first order with respect to the concentration of the catalyst and the ethyl cyanoformate but did not depend on the initial concentration of the substrate. A possible mechanism of the cyano‐ethoxy carbonylation reaction was proposed.

Oxazoline derivatives tagged with tosylated amino acids as recyclable organocatalysts for enantioselective allylation of aldehydes

A series of amino acid-based oxazoline compounds have been prepared and successfully applied to the enantioselective allylation reaction of aldehydes. The fine-tuning of the structure of the oxazolines led to (S,S)-4 as an efficient organocatalyst which gave homoallyl alcohols in good yield (up to 90%) and excellent ee (up to 99%) for a wide range of substrates including aromatic, hetero-aromatic and α,β-unsaturated aldehydes. The chiral organocatalyst was synthesized in three easy steps with an overall 88% yield and successfully recycled for up to three cycles. On the basis of the experimental observations and NMR studies, a probable mechanism was proposed for this reaction.

Asymmetric Cyanation Reactions

The asymmetric cyanation across C C, C O, and C N bonds ranks among the most important and well-studied reactions in asymmetric catalysis to achieve useful chiral building blocks for pharmaceuticals, agrochemicals, and specialty materials. The asymmetric cyanation reaction demands careful selection of a chiral catalyst and a cyanide source. A number of efficient and successful synthetic strategies have been developed that include asymmetric cyanation-utilizing enzyme, organocatalyst, and metal complexes as catalysts. As for the concern of the source of cyanide, inorganic cyanides, for example, NaCN and KCN; and organic cyanides, for example, trimethylsilyl cyanide, alkyl cyanoformates, acetone cyanohydrin, acetyl cyanide, alkyl cyanophosphorylates, etc. have been employed, depending upon the targeted substrates. Since the subject is vast, this chapter discusses in detail chiral-metal-complex-based catalytic asymmetric synthesis of cyanohydrins using different cyanide sources. An attempt is made to discuss the reaction mechanism involved in enantioselective cyanation reactions.