Pyrrolidines, enantioenriched 2-substituted

The chiral base i-BuLi/(—)-sparteine enantioselectively deprotonates the benzylic position of Ai-Boc-3-chloropropyl carbamates, which then cyclize to yield 2-substituted pyrrolidines with enantiomeric ratios greater than 90 10 (Scheme 63). Beak and coworkers showed that enantioselectivity is achieved through an asymmetric deprotonation to give an enantioenriched organolithium intermediate, which undergoes cyclization faster than epimerization. 

Astonishingly enough, enantioenriched lithiated cyclooctene oxides 142, originating from (—)-sparteine-mediated lithiation of 124 by i-BuLi/(—)-sparteine (11), could be trapped by external electrophiles, resulting in substituted epoxides 143 (equation 31) ° . Again, the use of i-PrLi furnished better enantioselectivities (approx. 90 10). Lithiated epoxides, derived from tetrahydrofurans and A-Boc-pyrrolidines, undergo an interesting elimination reaction . ... 

The asymmetric lithiation/substitution of Af-Boc-Af-(3-chloropropyl)-2-alkenylamines 395 by w-BuLi/(—)-sparteine (11) provides (5 )-Af-Boc-2-(alken-l-yl)pyrrolidines 397 via the allyllithium-sparteine complexes 396 (equation 106) . Similarly, the piperidine corresponding to 397 was obtained from the Af-(4-chlorobutyl)amine. Intramolecular epoxide openings gave rise to enantioenriched pyrrolidinols. Beak and coworkers conclude from further experiments that an asymmetric deprotonation takes place, but it is followed by a rapid epimerization a kinetic resolution in favour of the observed stereoisomer concludes the cyclization step. 

A-Boc-pyrrolidines are similarly deprotonated and furnish enantioenriched 2-substituted pyrrolidines (eq 6). ... 

Summary Our research on a-metalated organosilanes currently focuses on (aminomethyl)silanes containii a defined stereogenic center next to the silicon center. A synthetic route based on the preparation of 2-silyl-substituted pyrrolidines was developed. The racemic product could be synthesized by metalation of JV-Boc-pyrrolidine in the presence of TMEDA and conversion with the corresponding chlorosilane, whereas the enantioenriched form was achieved by metalation in the presence of the chiral amine (-)-sparteine. Subsequent metalation and transformation reactions yielded the formation of the corresponding (aminomethyl)(lithiomethyl)silane. 

Our ongoing research on (aminomethyl)(lithiomethyl)silanes focuses on modification of the substituents at the nitrogen center. The unprotected 2-silyl-substituted pyrrolidine 5 is a very useful starting point for the synthesis of different A -substituted pyrrolidines like rac-6. The racemic compound rac-S and the enantioenriched compound (iS)-5 could be s)mthesized by reaction of the Af-Boc-protected compound rac-2 or (S)-2 trifluoroacetic acid (TFA) [10]. In subsequent reactions it was possible to introduce a methyl group at the nitrogen center by conversion of rac-S with methyl... 

Efforts to extend the direct asymmetric lithiation and substitution from N-Boc-pyrrolidine to AT-Boc-piperidine have not been successful. Although a low yield of an enantioenriched product can be obtained from N-Boc-piperidine, competing reactions intervene, a result which is consistent with calculations [41]. 

Beak and coworkers also presented a convenient methodology for enantioselective syntheses of (S)-2-aryl-Boc-pyrrolidines 121 by intramolecular lithia-tion-substitution of arylmethyl-3-chloropropyl-Boc-amines [87]. Treatment of 120 with sec-BuLi/5 at -78°C led to the corresponding cyclized products 121 in moderate to good yields with high enantioselectivities of 96 4-98 2 (Scheme 37). The mechanism of the stereoinduction was established to be an enantioselective deprotonation by the sec-BuLi/5 complex to yield an enantioenriched lithiated species which undergoes rapid cyclization. 

In recent decades, chemists have demonstrated the proficiency of organo-catalysis as a useful synthetic tool for obtaining enantioenriched compounds. Thus, asymmetric organocatalysis has become a field of central importance along with biocatalysis and metal-mediated catalysis. In this chapter, we discuss the tremendous progress that has been achieved in the design and synthesis of various chiral 2-substituted pyrrolidine... 

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