Catalytic enantioselective phase-transfer alkylation

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.

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. 

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. 

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... 

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. 

Some phase-transfer catalytic asymmetric alkylation reactions of glycine imine derivatives have been explored to access natural products and biologically active compounds. For example, by employing an enantioselective phase-transfer catalytic alkylation, Kim et al. accomplished the first asymmetric total synthesis of the naturally occurring phenanthroindolizidine alkaloid (—)-antofine (Scheme 12.2) [102]. The key feature of this synthesis is the creation of the stereogenic center by reacting 65a with electrophile 66 in the presence of the dimeric catalyst 28 under the phase-transfer conditions. 

An enantioselective synthesis of both (R)- and (5)-a-alkylcysteines 144 and 147 is based on the phase-transfer catalytic alkylation of fert-butyl esters of 2-phenyl-2-thiazoline-4-carboxylic acid and 2-ort/ro-biphenyl-2-thiazoline-4-carboxylic acid, 142 and 145 <06JOC8276>. Treatment of 142 and 145 with alkyl halides and potassium hydroxide in the presence of chiral catalysts 140 and 141 gives the alkylated products, which are hydrolyzed to (R)- and (S)-a-alkylcysteines 144 and 147, respectively, in high enantioselectivity. This method may have potential for the practical synthesis of chiral a-alkylcysteines. 

E. J. Corey, F. Xu, M. C. Noe, A Rational Approach to Catalytic Enantioselective Enolate Alkylation Using a Structurally Rigidified and Defined Chiral Quaternary Ammonium Salt under Phase Transfer Conditions , J. Am. Chem. Soc, 1997,119,12414-12415. 

There are only a few reports on chiral phase transfer mediated alkylations". This approach, which seems to offer excellent opportunities for simple asymmetric procedures, has been demonstrated in the catalytic, enantioselective alkylation of racemic 6,7-dichloro-5-methoxy-2-phenyl-l-indanone (1) to form ( + )-indacrinone (4)100. /V-[4-(tnfluoromethyl)phenylmethyl]cinchoninium bromide (2) is one of the most effective catalysts for this reaction. The choice of reaction variables is very important and reaction conditions have been selected which afford very high asymmetric induction (92% cc). A transition state model 3 based on ion pairing between the indanone anion and the benzylcinchoninium cation has been proposed 10°. 

In 1999, in consideration of the readily structural modifications and fine-tuning of catalysts to attain sufficient reactivity and selectivity, Maruoka and coworkers designed and prepared the structurally rigid, chiral spiro ammonium salts of type 1 derived from commercially available (S)- or (R)-1,1 -bi-2-naphthol as a new C2-symmetric chiral phase-transfer catalyst, and successfully applied this to the highly efficient, catalytic enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester under mild phase-transfer conditions (Scheme 5.1) [7]. 

Enantioselective catalytic alkylation is a versatile method for construction of stereo-genic carbon centers. Typically, phase-transfer catalysts are used and form a chiral ion pair of type 4 as an key intermediate. In a first step, an anion, 2, is formed via deprotonation with an achiral base this is followed by extraction in the organic phase via formation of a salt complex of type 4 with the phase-transfer organocata-lyst, 3. Subsequently, a nucleophilic substitution reaction furnishes the optically active alkylated products of type 6, with recovery of the catalyst 3. An overview of this reaction concept is given in Scheme 3.1 [1],... 

Dolling UH, Davis P, Grabowski EJJ (1984) Efficient catalytic asymmetric alkylations, 1. Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysis. J Am Chem Soc 106 446... 

Catalytic Michael additions of a-nitroesters 38 catalyzed by a BINOL (2,2 -dihydroxy-l,r-bi-naphthyl) complex were found to yield the addition products 39 as precursors for a-alkylated amino acids in good yields and with respectable enantioselectivities (8-80%) as shown in Scheme 9 [45]. Asymmetric PTC (phase transfer catalysis) mediated by TADDOL (40) as a chiral catalyst has been used to synthesize enantiomeri-cally enriched a-alkylated amino acids 41 (up to 82 % ee) [46], A similar strategy has been used to access a-amino acids in a stereoselective fashion [47], Using azlactones 42 as nucleophiles in the palladium catalyzed stereoselective allyla-tion addition, compounds 43 were obtained in high yields and almost enantiomerically pure (Scheme 9) [48]. The azlactones 43 can then be converted into the a-alkylated amino acids as shown in Scheme 4. 

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