Catalytic asymmetric phase-transfer alkylation

Catalytic Asymmetric Phase-Transfer Michael Addition to oqfS-Unsaturated Esters 

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In the Park-Jew group s systematic investigation, two types of catalyst - the 1,3-phenyl- and 2,7-naphthyl-based dimeric ammonium salts - were selected as an efficient skeleton of chiral PTCs for the catalytic asymmetric phase-transfer alkylation... 

Scheme 6.2 Catalytic asymmetric phase-transfer alkylation of various electrophiles.

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... 

Jew, Park, and coworkers extended the substrate scope of phase-transfer catalytic alkylation to the oxazoline system in order to synthesize chiral a-alkyl serine derivatives. The authors chose phenyl oxazoline derivative 74 [106] as the substrate (Scheme 12.6). In the presence of Cj-symmetric chiral quaternary ammonium bromide (S,S)-31c, the asymmetric phase-transfer alkylation of 74 with alkyl halides, followed by acidic hydrolysis, provided chiral a-alkyl serines in very high yields and enantioselecti vities. 

Scheme 4.1 Synthesis of a-alkyl-a-amino acids via asymmetric phase-transfer catalytic alkylation ofbenzophenone imine glycine ester (A).

The phase-transfer benzylation of 2 with the catalyst (S)-12a having [1-naphthyl group on the 3,3 -position of the flexible biphenyl moiety proceeded smoothly at 0 °C to afford the corresponding alkylation product (R)-3 in 85% yield with 87% ee after 18 h. The origin of the observed chiral efficiency could be ascribed to the considerable difference in catalytic activity between the rapidly equilibrated, diaste-reomerichomo- and heterochiral catalysts namely, homochiral (S,S)-12a is primarily responsible for the efficient asymmetric phase-transfer catalysis to produce 3 with high enantiomeric excess, whereas the heterochiral (R,S)-12a displays low reactivity and stereoselectivity. 

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. 

In middle of the 1980s, efficient asymmetric phase-transfer reactions using catalytic amounts of Al-benzylcinchoninium chlorides were developed by researchers at Merck. This catalyst was able to alkylate 2-substituted-2-phenyl indanones with high ee (up to 94% ee) [20]. 

One class of application that readily highlights the enormous potential of asymmetric phase-transfer catalysis is the stereoselective ot-alkylation of different carbanion nucleophiles, in particular enolates. Although these types of transformations are most important in organic chemistry, there are stiU only a limited number of stereoselective catalytic methods available and the use of chiral PTCs represents one of the most versatile strategies to achieve such transformations. One example of special interest is the asymmetric a-alkylation of glycine Schiffbase 374 (Scheme 85)... 

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... 

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. 

Scheme 12.1 Asymmetric phase-transfer catalytic alkylation of glycine imine ester 65a.

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]. 

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

Acrylonitrile, polymerization, 120 Activity of phase-transfer catalysts Sjj2 reactions, 170-175 weak-nucleophile Sj.Ar reactions, 175-182 Acyltetracarbonyl cobalt compound, cleavage in the carboxyalkylation of alkyl halides, 150 Addition reactions, Michael, catalytic asymmetric, 69,70f... 

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°. 

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