Cyclic asymmetric benzylation

Asymmetric alkylation of P-keto carbonyl derivatives under phase-transfer conditions is a very convenient and useful way to construct a chiral quaternary carbon center. In 2002, Dehmlow and coworkers reported the asymmetric benzylation of the cyclic (3-ketoester, 2-(tert-butoxycarbonyl)cyclopentanone (70) in the presence of the cinchoninium PTC 72 in excellent chemical yield with 46% ee (Scheme 6.21) [46]. 

Other research groups also devoted their efforts toward the design and synthesis of new polymeric cinchona-based quaternary ammonium salts. Najera et al. [59] developed the catalyst 29 which incorporates a 9,10-dimethylanthracenyl bridge as a spacer, whereas Siva and Murugan [60] prepared the dimeric cinchonidinium salts 30 using a cyclic tetraamine spacer. Both catalysts exhibited good performance in the asymmetric benzylation of N-(diphenyhnethylene) glycine tert-butyl ester. 

Until this work, the reactions between the benzyl sulfonium ylide and ketones to give trisubstituted epoxides had not previously been used in asymmetric sulfur ylide-mediated epoxidation. It was found that good selectivities were obtained with cyclic ketones (Entry 6), but lower diastereo- and enantioselectivities resulted with acyclic ketones (Entries 7 and 8), which still remain challenging substrates for sulfur ylide-mediated epoxidation. In addition they showed that aryl-vinyl epoxides could also be synthesized with the aid of a,P-unsaturated sulfonium salts lOa-b (Scheme 1.4). 

While all of the aryl imine substrates examined for this Strecker methodology existed predominantly or exclusively as the E-isomers, this did not appear to be a requirement for high enantioselectivity as demonstrated in the asymmetric 42-cat-alyzed (2 mol% loading) hydrocyanation of the cyclic Z-imine 3,4-dihydroisoquino-line, which was converted to the corresponding adduct (88% yield, 91% cc) with the same sense of stereoinduction with respect to the benzylic stereogenic center as the examined acyclic E-imines (Schemes 6.41 and 6.42) [196]. 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

A fruitful approach to obtain asymmetric polymer synthesis was proposed by Overberger (126) who suggested that propagation could be influenced and optically active polymers could be synthesized by using optically active gegen-ions. Schmidt and Schuerch (127) followed up this suggestion and used boron trifluoride in conjunction with asymmetric Lewis bases (1-a-methyl benzyl alcohol, tosyl L-valine, camphor) to polymerize certain cyclic olefins. However, in spite of careful work and various modifications in reaction conditions, no optical activity was obtained in the polymers in this first attempt to test this ingenious hypothesis. 

The enantioselective a-benzylation of the lithium enolate of acyclic carboxamides, such as propionamides and butyramides, generated with CLA derived from original pen-tamines bearing several asymmetric centers has been reported495. Complementary, cyclic carboxamides such as perhydropyrimidinones lithium enolates, obtained from more classic Simpkins-type CLAs, were methylated or benzylated in toluene at —78 °C in the... 

Simple L-alanine, L-valine, L-norvaline, L-isolecucine, L-serine and other linear amino acids [ 121 ] or chiral amino acids with a binaphthyl backbone [ 122] and peptides have also been used as asymmetric catalysts [123,124,125,126]. Solid-supported proline-terminated peptides have been used for heterogeneous catalysis of the asymmetric aldol reaction [ 127]. Apart from proline and derivatives, other cyclic compounds such as 5,5-dimethyl thiazolidinium-4-car-boxylate (DMTC) [128], 2-fert-butyl-4-benzyl imidazolidinones [129], (l/ ,25)-2-aminocy-clopentanecarboxylic acid [130], (5 -5-(pyrrolidin-2-yl)tetrazole, (5)-l,3-thiazolidine-4-car-boxylic acid, (5)-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, and (5)-hydroxyproline are effective catalysts in asymmetric aldol reactions [126,131,132,133,134,135]. 

In 1976, using the parent quinine as a catalyst and 30% aqueous hydroperoxide as an oxidant, the asymmetric epoxidation of cyclic enones, such as naphthoquinones, was explored by Wynberg and coworkers [13]. However, the resulting enantioselec-tivity was minimal. Their further attempt under biphasic conditions with N-benzyl-quininium chloride 1 as the catalyst and t-BuOOH as the oxidant also resulted in very low enantioselectivities (up to 20% ee for the epoxidation of various cyclohexe-nones) [14]. However, the use of the dimeric form of Wynberg s catalysts 6 and 7 resulted in somewhat better (up to 63% ee with cyclohexenone) asymmetric... 

Recent developments tend to focus on the asymmetric aspects of stereoselective aldols but the diastereoselectivity is just as important. The cyclic ester 56 must of course form an E enolate and when the boron enolate -57 reacts with aldehydes the an//-aldol products 58 are formed with good stereoselectivity ranging from 4 1 to >20 1. The predominate isomer is that expected from the Zimmerman-Traxler transition state. The two benzylic-0 bonds can be cleaved by hydrogenation and the 2,3-dihydroxy acids anti-59 released in good yield.17... 

An interesting effect of imide and amine additives was observed for Ir-bcpm and Ir-binap catalysts. The catalyst performance for the hydrogenation of im-ines 7 was affected by the addition of phthalimide or perfluorophthalimide [26]. The highest enantioselectivity were obtained with the Ir-bcpm catalyst system 87% ee with F4-phthalimide and 86% with phthalimide. Primary or secondary amines were found to be useful co-catalysts for the asymmetric hydrogenation of N-benzyl-iV-(l-methylbenzylidene)amine and the cyclic imine 6 (R=Ph) with cationic Ir-binap (or Ir-tol-binap) catalysts [27]. For example, the addition of... 

Benzyl methylsulfide, thioanisol, and thiobenzamide were oxidized by chloroperoxidase, lactoperoxidase, and horseradish peroxidase to the respective sulfoxides. Whereas lactoperoxidase and horseradish peroxidase had low activities towards benzyl methylsulfide, thiobenzamide was efficiently oxidized by lactoperoxidase. Chloroperoxidase had high activity in halide-independent reactions towards all three substrates1251. This enzyme was also used for the asymmetric sulfoxidation of a series of cyclic sulfides. In all cases the (R)-sulfoxides were obtained. In the case of... 

Acetal Fission in Desymmetrization of 1,2-Diols. The asymmetric desymmetrization of cyclic i eso-l,2-diols was accomplished via diastereoselective acetal fission. After acetalization of ffiei >-l,2-diols with the C2-symmetric bis-sutfoxide ketone, the resulting acetal was subjected to base-promoted acetal fission, followed by acetylation or benzylation to give the desymmetrized diol derivatives. Interestingly, the counter-cation of the base had a remarkable effect on the diastereoselectivity of the reaction. While LHMDS produce the desired compound with low diastereoselectivity, 90% and >96% diastereomeric excesses were obtained... 

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