Enantioselective phase-transfer alkylation

J. J. Eddine, M. Cherqaoui, Chiral Quaternary Benzo-phenone Hydrazonium Salt Derivatives Efficient Chiral Catalysts for the Enantioselective Phase-Transfer Alkylation of Imines. Application to Synthesis of Chiral Primary Amines , Tetrahedron Asymmetry 1995, 6, 1225-1228. 

Having optimized the catalytic enantioselective phase-transfer alkylation system, the group explored the scope and limitations. A variety of electrophiles were reacted with the benzophenone imine glycine tert-butyl ester 1 catalyzed by 5 mol% of the selected chiral dimeric PTCs, benzene-linked-l,3-dimeric PTC 37, 2 -F-benzene-linked-1,3-dimeric PTC 41, and naphthalene-linked-2,7-dimeric PTC 39, at reaction temperatures of 0°C or — 20 °C (Scheme 4.8). 

Table 5.2 Catalytic enantioselective phase-transfer alkylation of glycine derivative 2 catalyzed by (S)-16Aa, (S)-16Ab, (S)-16Ba, and (S)-16Bb.

Table 5.3 Catalytic enantioselective phase-transfer alkylation of glycine derivative 2.

Scheme 3.17 Enantioselective phase-transfer alkylation catalyzed by 20.

E. J. Corey, Y. Bo, J. Busch-Peterson, Highly Enantioselective Phase Transfer Catalyzed Alkylation of a 3-Oxygenated Propionic Ester Equivalent Application and Mechanism , J. Am Chem Soc 1998, 120, 13000-13001. 

C. Lemaire, S. Gillet, S. Guillouet, A. Plenevaux, J. Aerts, A. Luxen, Highly enantioselective synthesis of no-carrier-added 6-[ F]fluoro-L-DOPA by chiral phase-transfer alkylation, Eur. J. Org. Chem. 13 (2004) 2899-2904. 

Table 5.7 Catalytic enantioselective synthesis of a,a-dialkyl-a-amino acids by phase-transfer alkylation.

These low selectivities were improved by changing the amine substituents of the catalysts 34 from diisopropyl/dicyclohexyl to C2-symmetric 2,5-dimethyl-pyrroline ring, leading to two diastereomeric catalysts 35 (Scheme 6.14), which were synthesized in the same way as catalysts 34 [9]. The catalytic competency of 35 was established using standard phase-transfer alkylation conditions to afford the alkylation product with up to 37% ee. Enantioselectivities obtained using diastereomers of the catalyst 35 were different, but not opposite, which suggests that the stereocenters function cooperatively in one diastereomer, but not in the other. 

In 1992, O Donnell succeeded in obtaining optically active a-methyl-a-amino acid derivatives 49 in a catalytic manner through the phase-transfer alkylation of p-chlorobenzaldehyde imine of alanine tert-butyl ester 48 with cinchonine-derived la as catalyst (see Scheme 4.16) [46]. Although the enantioselectivities are moderate, this study is the first example of preparing optically active a,a-dialkyl-a-amino acids by chiral phase-transfer catalysis. 

Kim et al. used an enantioselective catalytic phase transfer alkylation, together with a ring-closing metathesis for pyrrolidine ring constmction, to first synthesize the phenanthroindolizidine (-)-antofine [(-)-3] [63, 63]. Two similar approaches were developed, but only the later approach is illustrated in Scheme (8). As the key intermediate of this synthetic pathway, 77 is in enantiomerically pure form and was achieved by using a... 

Hughes, D. L. Dolling, U.-H. Ryan, K. M. Schoenewaldt,E. F. Grabowski, E.J.J., Efficient Catalytic Asymmetric Alkylations. 3. A Kinetic and Mechanistic Study of the Enantioselective Phase-Transfer Methylation of 6,7-Dichloro-5-methoxy-2-phenyl-l-indanone J. Org. Chem. 1987, 52, 4745. 

In 1999, Arai, Shioiri, and coworkers reported the use of a-fluorotetralone 61 as the efficient substrate for the preparation of optically active fluoro compounds by asymmetric phase-transfer alkylation (Scheme 6.18) [43]. From the screening of the reaction variables, the group found that enantioselectivity was influenced by the aryl part of the catalyst, and the salt 63 possessing pentamethylphenyl moiety was the optimal PTC for this alkylation. 

The phase transfer alkylation of Schiff bases has been extended to several other alkyl bromides as a route to new amino acids [24], and the enantioselectivities in these cases are comparable (50 to 70% ee) to those reported by O Donnell. In addition, the methodology has been used for the synthesis of a-methylamino acids, with ee s of about 50% [25]. Futher optimization using an 0-alkylated catalyst and a no solvent process with solid KOH/K2CO3 led to improved ee s of 70%... 

Summary. Asymmetric catalytic phase transfer alkylations are effective within a limited pool of substrates. No generalized catalyst is effective with a wide range of substrates instead, catalyst and conditions must be tuned for each reaction. The rationale for enantioselectivity has been probed by theory and experiment, but much work remains to unravel the details of the chemistry. 

Enantioselective phase-transfer catalysis (PTC) has been extensively applied for the alkylation, epoxidation, conjugate addition and related process, with the use of chiral ammonium salts being the typical transfer agent [293]. However, the related aldol... 

Kim S, Lee J, Lee T, Park HG, Kim D (2003) First Asymmetric Total Synthesis of (-)-Antofine by Using an Enantioselective Catalytic Phase Transfer Alkylation. Org Lett 5 2703... 

A few years later Maruoka and coworkers [52] investigated the influence of ultrasonic irradiation on an asymmetric phase-transfer alkylation of glycinate-benzophenone Schiff base catalyzed by a chiral C2-symmetric ammonium salt (lmol%) in toluene and 50% KOH aqueous solution (Scheme 21.22). In this case sonication also significantly enhanced the reaction rate and reduced the reaction time from 8 to 1 h. Moreover, the enantioselectivity of the product was comparable with those obtained in the reaction with conventional stirring. 

Biphenomycin B 11 is a 15-membered cyclic tripeptide isolated from the culture broths of Streptomyces filipinensis and S. griseorubuginosus. This compound displayed potent activity against Gram-positive, p-lactam-resistant bacteria, such as Streptococcus aureus. Enterococcus faecalis, or Streptococcus sp. The enantioselective total syntheses of biphenomycin B 11 using an asymmetric phase-transfer alkylation were reported by two groups. 

The catalytic enantioselective synthesis of ( )-paroxetine (69, Paxil GlaxoSmithKline, London, U.K.), which is a selective serotonin reuptake inhibitor being used for the treatment of depression, anxiety, and panic disorders, was executed as an application of the catalytic asymmetric mono -a-alkylation of 1,3-amide esters (Scheme 4.16). The characteristic feature of this protocol is the introduction of the C3-stereocenter first by the asymmetric phase-transfer alkylation before installing the C4-center by a diastereoselective Michael addition. Af,A -Di-p-methoxyphenyl malonamide... 

Hughes DL, Dolling UH, Ryan KM, Schoenewaldt EE, Grabowski, EJJ. Efficient catalytic asymmetric alkylations. 3. A kinetic and mechanistic study of the enantioselective phase-transfer methylation of 6, 7-dichloro-5-methoxy-2-phenyl-l-indanone. J. Org. Chem. 1987 52(21) 4745 752. 

Kim S, Lee J, Lee T, Park H, Kim D. First asymmetric total synthesis of (—)-antofine by using an enantioselective catalytic phase transfer alkylation. Org. Lett. 2003 5(15) 2703-2706. 

Ooi T, Takeuchi M, Kato D, Uematsu Y, Tayama E, Sakai D, Maruoka K. Highly enantioselective phase-transfer-catalyzed alkylation of protected a-amino acid amides toward practical asymmetric synthesis of vicinal diamines, a-amino ketones, and a-amino alcohols. J. Am. Chem. Soc. 2005 127(14) 5073-5083. 

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