Diamine Ligands for Asymmetric Catalysis: Facile Synthesis of C2-Symmetric Piperazines from Seebach’s Oxazolidinone

Abstract

C 2 -Symmetrical hemiaminal ethers and diamines with a piperazine core were synthesized starting from Seebach's oxazolidinone. The new methodology is based on the dimerization of α-amino aldehydes to bicyclic bishemiaminal ethers, followed by reduction to the corresponding diamines. Several enantiopure piperazine derivatives bearing either methyl or bulky groups including isopropyl and aryl at the bridgehead carbon atoms were obtained applying this methodology. Initial screening of new ligands in the copper-catalyzed asymmetric acylation of meso-1,2-diols produced promising results (up to 92% ee). Chiral amines, particularly the bistertiary diamines are extensively utilized in asymmetric reactions as organocatalysts 1a or in complexes with alkali as well as transition metals. 1b The easy availability of amines in enantiopure form and their well-known properties such as resistance to air oxidation in combination with a relatively low hazard level for environment, make chemical processes utilizing amines attractive for industry.Scheme 1 Literature synthesis of C 2 -symmetrical piperazine Ligands based on piperazine derivatives have recently gathered considerable attention due to their simple synthesis and high efficiency shown in a variety of reactions. 2,3 Within the large family of piperazines, the C 2 -symmetric diamines 1a 4 and 1b 2 appear a very capable set of ligands (Scheme 1). Enantiopure 1a can be easily obtained by lithium aluminum hydride reduction of a dimer, derived either from L-oxoglutamic acid 5 (compound 2) or alternatively, from L-proline 2,4a,b (compound 3). Shirai et al. 2 reported the preparation of dimethyl derivative 1b while targeting analogues 1a, di-substituted at the bridgehead carbon atom. Ligand 1b was used in the asymmetric acylation of several σ-symmetric 1,2-diols, showing in all cases both a higher reaction yield and a higher enantiomeric excess than 1a. The authors attempted to prepare more analogues of 1b with bridgehead substituents bulkier than the methyl group. However, probably due to the steric hindrance between the first alkyl group on the quaternary carbon atom and the approaching electrophile, the alkylation of diketopiperazine 3 with allyl-or benzyl bromides gave either predominantly or exclusively achiral trans isomers. Recently, we reported the synthesis of novel C 2 -symmetrical diamines with a piperazine core bearing an alkyl or aryl substituent at the bridgehead carbon atom. 6 The main step of our methodology is the base-catalyzed dimerization of the generated in situ aminoaldehyde 5 to the bishemiaminal inner ether 6 (Scheme 2). Since the quaternary stereogenic center located at the carbon atom N

Kinetic Resolution of dl-Hydrobenzoins Catalyzed by Copper(II) Complexes of C 2-Symmetric Thiophene-Derived Ligands

“…bis(4-methoxyphenyl)ethyl benzoate (4f) white solid,1 H NMR (300 MHz, CDCl 3 )  = 8 15. 8.06 (m, 2H), 7.64-7.55 (m, 1H), 7.49-7.43 (m, 2H), 7.15-7.08 (m, 4H), 6.79-6.73 (m, 4H), 6.03 (d J = 7.8 Hz, 1H), 5.03 (dd J = 7.8, 2.3 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 2.60 (d J = 2.9 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 )  = 165.8, 159.4, 159.3, 133.2, 131.2, 130.1, 129.7, 129.6, 129.0, 128.7, 128.5, 128.4, 113.6, 113.5, 80.5, 76.8, 55.2, 55.1; HRMS (ESI + ): [M-OH] + , found 361.1434.…”

“…[7][8][9] Complexes of Cu(II) and bisoxazolines or related analogues are the catalysts most frequently used for this purpose. 10 On the other hand, chiral amines [11][12][13] or their Cu(II) complexes [14][15][16] have been used for acylative desymmetrization of meso-diols including meso-hydrobenzoin. Few of these catalysts can accept both dl-and meso-hydrobenzoins as substrates.…”