Intramolecular reactions asymmetric alkylation

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

Pyrrolidines are an important class of five-membered heterocycles with noteworthy biological properties [46]. In addition to pharmaceutical applications, the pyrrolidine moiety has also been widely used as a chiral auxiliary for asymmetric synthesis [47]. Although many elegant syntheses of chiral nonracemic pyrrolidines have been reported within the past decade or so [48-50], an alternative approach based on the intramolecular reaction of an azide and organoborane has been developed very recently [51-53], This approach utilizes the hydroboration-azide alkylation tandem reaction as a key sequence, taking advantage of the efficient stereocon-trolled steps. Scheme 20 shows an application of the synthesis of 3-substituted 5-(2-pyrrolidinyl)isoxazole which has been found to have nanomolar activity, comparable to (5)-nicotine, against whole rat brain [54]. 

This type of allylic alkylation has been applied in the asymmetric total synthesis of (—)-anatoxin-a (7) using a N-nucleophile and Pd-based bpchH2 complexes in an intramolecular reaction to form the 9-azabicyclo[4.2.1]non-2-ene system (eq 3). ... 

Asymmetric Alkylation. 4-Pseudoephedrine ([IS, 2S]-(+)) is a commodity chemical employed in over-the-counter medications with annual worldwide production in excess of 300 metric tons. The enantiomer, /-pseudoephedrine, is also readily available in bulk and is inexpensive. Pseudoephedrine has been shown to be highly effective as a chiral auxiliary in asymmetric alkylation reactions. Treatment of either enantiomer of pseudoephedrine with carboxylic acid chlorides and anhydrides leads to efficient and selective iV-acylation to form the corresponding tertiary amide derivatives (Table 1). Typically, the only by-product in the acylation reactions is a small amount (<5%) of the A,0-diacylated product, which is easily removed by crystallization or flash column chromatography. Because intramolecular 0- -N acyl transfer within pseudoephedrine 3-amino esters occurs rapidly, and because the A-acyl form is strongly favored under neutral or basic conditions, products arising from (mono)acylation on oxygen rather than nitrogen are not observed. 

IS,3S,7R)- methyl-a- hiniachalene 4 Sandlly [Lutzornya iongipalpis) Ms Intramolecular DieJs-Alder reaction catalyzed by EJ AICI and Evans asymmetric alkylation [180] [I8IJ... 

The products of the asymmetric alkylation have been used as key building blocks in syntheses of morphanes, phyllanthocin, and periplanone B natural products. In the case of the synthesis of the morphane skeleton, a phenolic nucleophile was reacted with cyclohexenyl methyl carbonate and the resulting ether was subjected to a europium-induced Claisen rearrangement followed by an intramolecular aldehyde-ene reaction to generate the key tricyclic intermediate. Scheme 27 [56]. 

S.3S.7R)- mcthyl-u- himachaliMie Sand lly Lulzmmii longipalpix) Ms Intramolecular Diels-Alder reaction catalyzed by LtjAICI and Leans asymmetric alkylation [1801 [I8IJ... 

The intramolecular organocatalytic asymmetric a-alkylation of aldehydes was developed by Vignola and List in 2004 [34]. Experimentally, it was found that 2-methylproline was a much better catalyst than proline itself, and Methylamine accelerated the reaction. A subsequent theoretical study by Fu, List, and Thiel [35] concluded that the reaction proceeds via an enamine displacement of the halogen. Triethylamine was found to provide a salt bridge between the carboxylic acid and the departing halide, and the stereoselectivity of the reaction was shown to arise from preferred cyclization (by 1 kcal/mol) of an a ri-enamine relative to that of the syn-enamine (Figure 2.12). The calculations also indicated that the enhanced enantio-selectivity of the 2-methylproline catalyzed aldol reaction compared with the proline-catalyzed process is due to the inherently larger steric interactions between the methyl and the aldehyde substituent in the syn transition state. 

The 1,5-anti-aldol reaction was performed with chiral boron enolate of 325 and aldehyde 327, prepared by Evans asymmetric alkylation, cross metathesis, and Wittig homologation (Scheme 72), to afford 324 with a 96 4 diastereoselectivity. Stereoselective reduction of C9-ketone provided the 5y -l,3-diol, which was exposed to catalytic f-BuOK to give 2,6-cis-tetrahyderopyran 333 via an intramolecular Michael reaction. Finally, methyl etherification, deprotection, hydrolysis of ester, and Yamaguchi macrolac-tonization yielded the leucascandrolide macrolide 201 (Scheme 73). 

Asymmetric synthesis of 3,4-dihydrocoumarin 41 was achieved by rhodium(I) catalyzed intramolecular reaction of phenol-substituted cydobutanone 42 (Scheme 3.21) [33]. When the reaction of 3,3-disubstituted cyclobutanones was performed in the presence of electron-deficient alkenes, the arylrhodium species generated via 1,4-rhodium shift underwent addition to the alkenes, providing 5-alkylated dihydrocoumarins (Scheme 3.22). 

Lepine and Zhu accomplished total synthesis featuring judicious use of the PTC 1-catalyzed asymmetric alkylation of Schiff base 1 and a microwave-assisted intramolecular Suzuki-Miyaura reaction for the formation of... 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

A few intriguing developments in the area of tetrahydro-P-carboline synthetic methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-P-carbolines from L-tryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 

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