Recent advances in synthetic methods for the direct α-functionalization of saturated cyclic amines are described. Methods are categorized according to the in situ formed reactive intermediate (α-amino cation, α-amino anion, and α-amino radical). Transition-metal-catalyzed reactions involving other intermediates have been treated as a separate and fourth class.
Two strategies, "hydrogenation-hydride reduction" and "quaternization-hydride reduction", are reported that make use of mild reaction conditions (room temperature) to efficiently remove the N-pyridin-2-yl directing group from a diverse set of C-2-substituted piperidines that were synthesized through directed Ru-catalyzed sp(3) C-H functionalization. The deprotected products are obtained in moderate to good overall yields irrespective of the strategy followed, indicating that both methods are generally equally effective. Only in the case of 2,6-disubstituted piperidines, could the "quaternization-hydride reduction" strategy not be used. The "hydrogenation-hydride reduction" protocol was successfully applied to trans- and cis-2-methyl-N-(pyridin-2-yl)-6-undecylpiperidine in a short synthetic route toward (±)-solenopsin A (trans diastereoisomer) and (±)-isosolenopsin A (cis diastereoisomer). The absolute configuration of the enantiomers of these fire ant alkaloids could be determined via VCD spectroscopy.
Kinetic resolution is an important method for the separation of racemates into their component enantiomers. Thiols are precursors to a variety of organosulfur compounds, with high utility in both chemistry and chemical biology, yet there is a surprising dearth of methodologies for their direct and efficient catalytic kinetic resolution. Here, we demonstrate an organocatalytic process involving the highly enantioselective desymmetrization of an achiral electrophile with the simultaneous kinetic resolution of a racemic thiol. The preparative potential of the methodology is exemplified by the synthesis of a drug precursor antipode in excellent yield and enantioselectivity as a by-product of a process that also resolves a sec-thiol substrate with a selectivity of S = 226 (that is, both thiol antipodes produced in >95% ee at 51% conversion). In a second example a racemic sec-thiol representing the stereocentre-containing core of the anti-asthma drug (R)-Montelukast was resolved with synthetically useful selectivity under mild conditions.
A systematic study concerning the immobilisation onto magnetic nanoparticles of three useful classes of chiral organocatalyst which rely on a confluence of weak, easily perturbed van der Waals and hydrogen bonding interactions to promote enantioselective reactions has been undertaken for the first time. The catalysts were evaluated in three different synthetically useful reaction classes: the kinetic resolution of sec-alcohols, the conjugate addition of dimethyl malonate to a nitroolefin and the desymmetrisation of meso anhydrides. A chiral bifunctional 4-N,N-dialkylaminopyridine derivative could be readily immobilised; the resulting heterogeneous catalyst is highly active and is capable of promoting the kinetic resolution of sec-alcohols with synthetically useful selectivity under process-scale friendly conditions and has been demonstrated to be reusable in a minimum of 32 consecutive cycles. The immobilisation of a cinchona alkaloid-derived urea-substituted catalyst proved considerably less successful in terms of both catalyst stability and product levels of enantiomeric excess. An immobilised cinchona alkaloid-derived sulfonamide catalyst was also prepared, with mixed results: the catalyst exhibits outstanding recyclability on a par with that associated with the successful N,N-dialkylaminopyridine analogue, however product enantiomeric excess is consistently lower than that obtained using the corresponding homogeneous catalyst. While no physical deterioration of the heterogeneous catalysts was detected on analysis after multiple recycles, in the cases of both the conjugate addition to nitroolefins and the desymmetrisation of meso anhydrides, significant levels of background catalysis by the nanoparticles in the absence of the organocatalyst was detected, which explains in part the poor performance of the immobilised organocatalysts in these reactions from a stereoselectivity standpoint. It seems clear that the immobilisation of sensitive chiral organocatalysts onto magnetite nanoparticles does not always result in heterogeneous catalysts with acceptable activity and selectivity profiles, and that consequently the applicability of the strategy must be ascertained (until more data is available) on a case-by-case basis.
Bifunctional urea-based cinchona alkaloid derivatives have been shown to promote highly efficient DKR reactions of azalactones using an alcohol nucleophile. The optimum catalyst is remarkably insensitive to the steric bulk of the amino acid residue, allowing alanine-, methionine-, and phenylalanine-derived azalactones to undergo DKR with unprecedented levels of enantioselectivity using a synthetic catalyst. The first DKR of these substrates by thiols and the highly enantioselective desymmetrization of a meso-glutaric anhydride by thiolysis are also reported.
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