Alkylation asymmetric intramolecular

Very recently, the first catalytic asymmetric intramolecular a-alkylation of an aldehyde has been achieved by the List group [70]. In the presence of a-methyl-substituted L-proline, (S)-61, as organocatalyst, ring-forming reactions leading to chiral cyclopentanes, cyclopropanes, and pyrrolidines proceed with high enantioselectivity - in the range 86-96% ee. Selected examples are shown in Scheme... 

Uraguchi D, Terada M (2004) Chiral Brpnsted acid-catalyzed direct Mannich reactions via electrophilic activation. J Am Chem Soc 126 5356-5357 Vignola N, List B (2004) Catalytic asymmetric intramolecular alpha-alkylation of aldehydes. J Am Chem Soc 126 450-451... 

Surprisingly, little follow-up work on this idea of small molecule asymmetric catalysis appeared for the next 25 years. In the late 1980s, Agami reported the asymmetric intramolecular aldol reaction of acyclic diketones with (S)-proline as the catalyst. It was not nntil the twenty-first centnry, however, when this notion of organocatalysts became fnlly exploited. List and Barbas ° pioneered enam-ines as catalysts for aldol and Mannich and related reactions. MacMillan has developed a variety of imininm-based catalysts prodncing large asymmetric indnction for Diels-Alder chemistry, Friedel-Crafts alkylations, Mnkaiyama-Michael and cyclopropanation " reactions. 

Aillaud, I., Lyubov, D., Collin, J. et al. (2008) Chiral amido alkyl rare earth complexes a new family of asymmetric intramolecular hydroamination catalysts. Organometallics, 27, 5929. 

More recently, asymmetric intramolecular carbolithiation was described, either with a remote chiral center in a suitable position to promote a diastereofacial differentiation of the olefin [130] or with a chiral organolithium derivative [131]. In the former case, alkylation... 

Vignola, N., List, B. Catalytic asymmetric intramolecular a-alkylation of aldehydes. J. Am. Chem. Soc. 2004,126, 450-451. 

Scheme 11.6 Asymmetric intramolecular a-alkylation of aliphatic aldehydes catalysed by (S)-proline (1) and (S)-a-2-methyl-proline (7a).

In contrast to the Rh-catalyzed asymmetric intramolecular direct C—H bond functionalization reactions described above, their asymmetric inter-molecular variants have been rarely explored. In 2000, Murai and co-workers reported a Rh-catalyzed intermolecular asymmetric C—H activation/olefin coupling reaction of achiral biaryl pyridine (132) or isoquinoline derivatives to deliver axially chiral biaryls (133) (Scheme 5.46a). Although both the efficiency (up to 37% yield) and the enantioselectivity (up to 49% ee) of the reaction were only moderate, this protocol provided an alternative method for the synthesis of optically active biaryl compounds. To some extent, this reaction was similar to a formal dynamic kinetic resolution. The two atropisomers of the biaryl starting materials could interconvert with each other freely due to a low inversion energy barrier. A properly chosen chiral catalyst could react preferentially with one atropisomer. The increased steric bulkiness of the final alkylated products can prevent the epimerization and the biaryl compounds possessing a stable axial chirality are established. However, due to the relatively low efficiency of the catalyst, the yields of the desired products are generally low and the starting materials can be recovered (Scheme 5.46b). 

Table 6.15 Asymmetric intramolecular AFC alkylation for the synthesis of tetrahy-drocarbazoles 176 reported by Bandini.

Seheme 6.88 Asymmetric intramolecular AFC-type allylic alkylation of phenols reported by You and by Hamada. 

High yields of 2-substituted chromans are readily attained from the asymmetric intramolecular oxa-Michael addition reaction of phenols bearing an (f -a,P-unsaturated ketone or thioester moiety mediated by a cinchona-alkaloid-urea-based bifunctional organocatalyst (140BC119). Molecular iodine-catalyzed reaction of phenols with a,P-unsaturated alcohols affords a wide range of 2,2-disubstituted chromans (14T5221). Chiral derivatives result from the intramolecular allylic alkylation of phenols bearing an... 

Dounay, A.B., Hatanaka, K., Kodanko, J. et al. (2003) Catatytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective s3mthesis of 3-alkyl-3-aryl oxindoles by catalytic asymmetric intramolecular Heck reactions. J. Am. Chem. Soc., 125, 6261-71. 

Naturally occurring alkaloid anatoxin-a, known to induce respiratory paralysis and possessing an unusual 9-azabicyclo[4.2.1]nonane skeleton, was recently synthesized by Trost and Oslob via an asymmetric intramolecular allylic alkylation (Scheme 39). The alcohol 179, prepared from 4-bromo-l-butene and ethylformate, was efficiently converted to functionalized cyclooctadiene 180 within six steps. Asymmetric cyclization was performed with a catalytic amount of Pd(0) and several ligands to enhance the enantioselectivity. A new chiral ligand, the (5,5)-l-(2-diphenylphosphinobenzamido)-2-(2-pico-linamido)cyclohexane, (5,5)-182, was synthesized to alleviate the unfavorable steric interaction and induced under smooth conditions the formation of cyclic 181 in 90% yield and 88% ee. The ester 181 was then converted to the methyUcetone, which was desulfonated to give (-)-anatoxin-a. 

Several other mechanistically distinct metal-catalyzed dearomatization procedures have been reported, and almost all involve phenol or naphthol derivatives undergoing dearomatization via intramolecular transformations. Intramolecular Pd- and Rh-catalyzed C4-arylation and alkylation of /)ara-substituted phenols has been used to construct compounds of general structure 82 (Fig. 15.1) [86]. These reactions rely on generation of electrophilic aryl or alkyl o-metal complex intermediates that participate in tandem C4 metalation-reductive elimination with an attached phenol. Ruthenium- and Pt-catalyzed reactions of naphthalenes and alkynes deliver spirocyclic products such as 83 [87, 88]. An asymmetric intramolecular naphthalene dearomatization catalyzed by Pd(0)-phosphine complexes has been used to prepare carbazole derivatives 84 in good enantiomeric excess from l-(AI-2-bromophenyl)aminonaphthalene precursors [89]. 

Homillos V, van Zijl AW, Feringa BL (2012) Catalytic asymmetric synthesis of chromenes and tetrahydroquinolines via sequential allylic alkylation and intramolecular Heck coupling. Chem Commun 48 3712-3714... 

Scheme 17 Tandem asymmetric allylic alkylation and intramolecular Heck coupling...

The a-alkylation of carbonyl compounds is a key carbon-carbon bond forming reaction in organic chemistry. Despite the widespread apphcations of this method, a general asymmetric intramolecular a-alkylation via enamine catalysis has proven to be extremely challenging because of catalyst alkylation, or racemization of products in the reaction. List and coworkers developed an intramolecular a-alkylation of aldehydes by using (S)-a-methylproline (15) as the catalyst [10]. To eliminate the influence of the by-product HX, a stoichiometric amount of NEts was added. A diversity of chiral cyclopentanes and pyrrolidines 17, or cyclopropanes 19, could be obtained in high yields and ees (Scheme 36.5). 

In 2011, a metal-free asymmetric intramolecular allylic alkylation promoted by a chiral A(-triflylphosphoramide 12b was achieved by Rueping et al. (Scheme 2.29). The phenol 96 was believed to undergo organic ion-pair catalytic procedure to furnish optically active 2/f-chromenes 97 in good yields and excellent enantioselectivities [40]. 

Watzke A, Wilson RM, O Malley SJ, Bergman RG, Ellman JA. Asymmetric intramolecular alkylation of chiral aromatic imines via catalytic C—H bond activation. Synlett 2007 2383-2389. 

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). 

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>. 

Nakagawa devised a concise synthetic route to physostigimine (169) where the key step involves the alkylative cyclization of 1,3-dimethylindole (167) with (Z)-aziridine catalyzed by Sc(OTf)3 and TMSC1 to give 168, which, in turn, can be converted into 169 . A similar asymmetric approach to this natural product was also developed by these authors via treatment of tryptophan carbamates with the Corey-Kim reagent so as to induce intramolecular cyclization to the pyrrolo-indole skeleton . 

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