Pd(ii)-catalyzed alkylation of unactivated C(sp3)–H bonds: efficient synthesis of optically active unnatural α-amino acids

Abstract

A palladium-catalyzed alkylation of primary and secondary C(sp 3 )-H bonds with alkyl iodides and/or bromides for the synthesis of optically active unnatural a-amino acids (a-AAs) is described. This process is scalable and tolerates a variety of functional groups with complete retention of chirality, providing an efficient new strategy for the synthesis of various unnatural a-amino acid derivatives.Unnatural a-amino acids (a-AAs) are key structural motifs of peptides, peptidomimetics and many other pharmaceutically important compounds. 1 Synthetic derivatives of biologically relevant peptides incorporating unnatural a-AAs oen display interesting pharmacological activity, sometimes with increased potency and enzymatic stability relative to their native counterparts. Apart from this, they have been successfully used as chiral ligands/catalysts and as chiral pool building blocks in asymmetric catalysis and total synthesis. 2 As a consequence, the chemical synthesis of these valuable compounds has received tremendous interests. 3 Traditionally, optically active unnatural a-AAs can be obtained through chemical and enzymatic resolutions of the corresponding racemates or through asymmetric synthesis. However, considering the widespread availability of natural a-amino acids, an attractive approach from the perspectives of atom-and step-economy would be to use them as substrates and perform palladium-catalyzed direct C-H alkylation to access their unnatural counterparts.However, Pd-catalyzed alkylation of unactivated C(sp 3 )-H with alkyl halides remains one of the most difficult transformations in transition-metal-catalyzed C-H functionalization reactions. 4,5 The difficulties of developing such a reaction stem from the following fundamental challenges: [4][5][6] (1) aliphatic C(sp 3 )-H bonds are signicantly more resistant to Pd insertion than C(sp 2 )-H bonds, and it is extremely difficult for the catalyst to distinguish among the many chemically similar C-H bonds on the substrate; (2) alkyl halides are electron-rich and therefore Scheme 1 Pd-catalyzed alkylation of unactivated C(sp 3 )-H bonds.

Divergent and Stereoselective Synthesis of β‐Silyl‐α‐Amino Acids through Palladium‐Catalyzed Intermolecular Silylation of Unactivated Primary and Secondary C−H Bonds

“…Pd(OAc) 2 (Stream), Ag 2 CO 3 (Adamas) were purchased from above mentioned company and used without additional purification. Other chemical reagents were commercially available and directly used without any further purification.…”

“…General Procedure for the Synthesis of 2a-2j via Pd-Catalyzed Monoarylation of Alanine Derivative 1 [1] To a 100-mL vial was added 1 (690.7 mg, 2.0 mmol), Pd(OAc) 2 (44.5 mg, 0.2 mmol), aryl iodide (2.4 mmol, for several specific reactions, 3.0 mmol of aryl iodide was used), AgBF 4 (506.2 mg, 2.6 mmol), and t-BuOH/DCE (10 mL + 5 mL). The mixture was stirred at 75 o C for 4 hours (for several specific substrates, the reactions were stirred for 24 hours).…”

“…2a-2j are known compounds. [1] General Procedure for the Synthesis of 2k via Pd-Catalyzed Alkylation of Alanine Derivative 1 [2] To a 30-mL resealable Schlenk flask was added N-phthaloyl-alanine 8-aminoquinoline amide (1) (0.2 mmol), Pd(OAc) 2 (4.5 mg, 0.02 mmol), iodomethane (0.3 mmol), Ag 2 CO 3 (0.16 mmol), S4 (BnO) 2 POOH (0.06 mmol), DCE/t-BuOH (1.5 mL, v/v = 1:1). The flask was then charged with N 2 .…”

“…2k is known compound. [2] General Procedure for synthesis of compound 5 [3] Compounds 5d, 5h, 5j and 5t were prepared from the corresponding carboxylic acids and 8-aminoquinoline (8-AQ). Other Compounds (5a-5c, 5e-5g, 5i, 5k-5s, 5u and 5v) are known compounds.…”

“…Other Compounds (5a-5c, 5e-5g, 5i, 5k-5s, 5u and 5v) are known compounds. [3] OH O 1) (COCl) 2 , DMF (cat.) DL-/L-1 were prepared following the literature procedure.…”