Alkyl transfer, catalytic enantioselective

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°. 

Principles. How shall we proceed toward catalytic asymmetric induction Scheme 5 illustrates a possible way to achieve enantioselective alkylation by using a small amount of chiral source. Under certain conditions, the presence of a protic chiral auxiliary HX can catalyze the addition of organometallic reagent, R2M, to a prochiral carbonyl substrate by way of RMX. To obtain sufficient chiral efficiency, the anionic ligand X must have a three-dimensional structure that allows differentiation between the diastereomeric transition states of the alkyl transfer step. In addition, unlike in stoichiometric reactions, the rate of... 

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). 

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]. 

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.

Recently, Jorgensen reported the first example of a catalytic enantioselective vinylic substitution reaction (Scheme 11.14). With a bulky 1-adamantylcarbonyl group modified phase-transfer catalyst lOd as the catalyst, the reaction between alkyl cyclopentanone-2-carboxylates (53a) with (ZJ-P-cholro-l-phenylpropenone (63a) proceeded smoothly, affording the product 64a with Z/f > 95 5 and 94% ee [50]. As for the trisubstituted alkene 64b, the a-iodine atom was tolerated in the catalytic reaction. 

Enantioselective alkylations have been achieved using modified MCM-41 materials.135 Mesoporous templated MCM-41s with covalently linked chiral ephedrine are active heterogeneous chiral auxiliaries in the enantioslective alkylation of benzaldehyde by diethylzinc. Lower rates, selectivities and enantioselectivities are obtained under heterogeneous conditions compared to homogeneous catalysis. This can be explained either by the participation of the uncovered surface to the racemic alkyl transfer or by a restricted accessibility to the catalytic sites in the heterogeneous reactions. 

Zhu and co-workers [77] have successfully developed the first organocatalytic enantioselective three-component Povarov reaction for the efficient synthesis of enantiomerically enriched (2,4-cis)-4-amino-2-aryl(alkyl)-tetrahydroquinolines. To illustrate the power of this novel catalytic enantioselective three-component Povarov reaction, they applied this methodology to the short and efficient synthesis of torcetrapib (188), a potent cholesteryl ester transfer protein (CETP) inhibitor (Scheme 17.31). Reaction of 4-trifluoromethylaniline 184, propionaldehyde 18, and enecarbamate 185 using phosphoric acid catalyst 186 afforded tetrahydroquino-line 187 in 57% yield with 93% ee. Ethoxycarbonylation, deprotection/acylation, and benzylation provided torcetrapib (188) in four steps with 32% overall yield. 

Within the area of PTC, purely synthetic chiral quaternary oninm salts have also been developed. For example, in 1999 Marnoka and co-workers prepared structurally rigid, chiral spiroammoninm salts of type 107 as new C2-symmetric phase-transfer catalysts and successfully applied them to the highly efficient, catalytic enantioselective alkylation of 106 under mild conditions. In general, 1 mol% of 107 promotes efficient alkylation, although the catalyst loading can be reduced to 0.2mol% without a decrease in ee (Scheme 18). 

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... 

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 efficient enantioselective total synthesis of (—) -cis-clavidpitic acid was reported by Park and coworkers (Scheme 12.3) [103]. The asymmetric phase-transfer catalytic alkylation of 65a with 68 was employed as the key step, producing the urmatural oi-amino acid derivative 69 for the introduction of the 5S chirality. Starting from a glycine derivative 65a, Maruoka and coworkers successfully developed a strategy for the asymmetric synthesis of cyclic amino acids having a piperidine or azepane core structure by the combination of a phase-transfer catalytic asymmetric alkylation and a subsequent diastereoselective reductive amination. This approach allows the... 

The Maruoka group described an efficient enantioselective synthesis of optically active a-methyl serine derivatives by using their structurally simpHfied catalyst (S)-36b under mild phase-transfer conditions [107]. The asymmetric synthesis of a-alkyl cysteines, a-alkyl-a,p-diamino propionic acids, a-alkyl homoserines, and a-alkyl homocysteines was also carried out via the asymmetric phase-transfer catalytic a-alkylation of thiazoline-4-carboxylic acid tert-butyl esters 75, imidazoHne-4-carboxylic acid tert-butyl esters 76, and the six-membered ring substrates 77 and 78 [108]. 

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