Fraser F. Fleming

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

Fraser F. Fleming,* Lihua Yao, P. C. Ravikumar, Lee Funk, and Brian C. Shook Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, Mylan Pharmaceuticals Inc., 781 Chestnut Ridge Road, Morgantown, West Virginia 26505, and Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477

Nitrile-containing natural products

Naturally occurring nitriles† comprise a small and surprisingly diverse set of secondary metabolites. The structures vary from simple, long-chain alkanenitriles to architecturally complex structures such as the calyculins, with new, more complex metabolites being continually reported. The number of nitrilecontaining natural products has risen from 33, in a 1981 review,3 to more than 1204 (excluding cyanogenic glycosides) and now includes metabolites from both terrestrial and marine sources.2 The increasing number of nitrile-containing natural products highlights the need for a general classification of these compounds with this review classifying metabolites according to the hybridization of the nitrile-bearing carbon. Three general categories result; alkanenitriles, a,b-unsaturated nitriles, and aromatic nitriles. This classification emphasizes the amino acid origin of the nitriles and combines some previous sub-groups into structurally-related classes. Nitrile-containing natural products are known to be derived from amino acids in plants,5 arthropods,6 bacteria and fungi1 (Scheme 1). N-Hydroxylation and decarboxylation of amino acids afford aldoximes 3 that are enzymatically converted to the corresponding nitrile 4 through a sequence that appears to be considerably more complex than a simple dehydration.7 Cyanogenic glycosides are derived from these nitriles by a stereoselective hydroxylation–glycosylation sequence.8 Glucosinolates provide another biosynthetic route to nitrilecontaining metabolites. The biosynthesis of glucosinolates 6 is closely related to that of nitriles in proceeding through an aldoxime intermediate.9 Hydrolysis of glucosinolates affords numerous metabolites, including nitriles, where the formation of nitriles results from a complex dependence on pH, co-factors, and the nature of the substituent.10 Glucosinolate hydrolysis often occurs during cooking of Brassica crops (such as cabbage, brussel sprouts, and cauliflower) leading to increased levels of nitriles from these sources.11 2 Alkanenitriles

Catalytic Isonitrile Insertions and Condensations Initiated by RNC–X Complexation

Isonitriles are delicately poised chemical entities capable of being coaxed to react as nucleophiles or electrophiles. Directing this tunable reactivity with metal and non-metal catalysts provides rapid access to a large array of complex nitrogenous structures ideally functionalized for medicinal applications. Isonitrile insertion into transition metal complexes has featured in numerous synthetic and mechanistic studies, leading to rapid deployment of isonitriles in numerous catalytic processes, including multicomponent reactions (MCR). Covering the literature from 1990-2014, the present review collates reaction types to highlight reactivity trends and allow catalyst comparison.

Pd-Catalyzed α-Arylation of Nitriles and Esters and γ-Arylation of Unsaturated Nitriles with TMPZnCl·LiCl

Using TMPZnCl·LiCl as a kinetically highly active base, nitriles and esters undergo a Pd-catalyzed α-arylation under mild conditions. Remarkably, in the case of α,β- or β,γ-unsaturated nitriles, a regioselective γ-arylation or a γ-alkenylation is observed.

Metalated nitriles: N- and C-coordination preferences of Li, Mg, and Cu cations

(13)C NMR analyses of a series of metalated arylacetonitriles and cyclohexanecarbonitriles with the synthetically relevant metals Li, Mg, and Cu identifies the influence of the carbon scaffold and the nature of the metal on the preference for N- or C-metalation.

Cyclic Metalated Nitriles: Stereoselective Cyclizations to cis- and trans-Hydrindanes, Decalins, and Bicyclo[4.3.0]undecanes

Metalated nitriles are nucleophilic chameleons whose precise identity is determined by the nature of the metal, the solvent, the temperature, and the structure of the nitrile. The review surveys the different structural types and their cyclization trajectories to show how to selectively tune the metalated nitrile geometry for stereoselective cyclizations to a variety of cis or trans hydrindanes, decalins, and bicyclo[4.3.0]undecanes.

Allylic and Allenic Halide Synthesis via NbCl5- and NbBr5-Mediated Alkoxide Rearrangements

Addition of NbCl(5) or NbBr(5) to a series of magnesium, lithium, or potassium allylic or propargylic alkoxides directly provides allylic or allenic halides. Halogenation formally occurs through a metalla-halo-[3,3] rearrangement, although concerted, ionic, and direct displacement mechanisms appear to operate competitively. Transposition of the olefin is equally effective for allylic alkoxides prepared by nucleophilic addition, deprotonation, or reduction. Experimentally, the niobium pentahalide halogenations are rapid, afford essentially pure (E)-allylic or -allenic halides after extraction, and are applicable to a range of aliphatic and aromatic alcohols, aldehydes, and ketones.

Metalated nitriles: internal 1,2-asymmetric induction.

Alkylations of conformationally constrained acyclic nitriles containing vicinal dimethyl groups and an adjacent phenyl group or trisubstituted alkene are exceptionally diastereoselective. Probing the alkylation stereoselectivity with a series of C- and N-metalated nitriles implicates a reactive conformation in which an sp2-hybridized substituent projects over the metalated nitrile to avoid allylic strain. Steric screening thereby directs the electrophilic attack to the face of the metalated nitrile opposite the projecting substituent. Excellent stereoselectively is maintained in a diverse range of alkylations that efficiently install quaternary centers, even with isopropyliodide in which a contiguous array of tertiary-quaternary-tertiary stereocenters is created! Screening the conformational requirements with a series of acyclic nitriles and esters reveals the key structural requirements for high selectivity while providing a robust, predictive model that accounts for comparable ester alkylations affording the opposite diastereomer! The intensive survey of metalated nitrile alkylations identifies the key structural features required for high 1,2-asymmetric induction, addresses the long-standing challenge of asymmetric alkylations with acylic metalated nitriles, and provides a versatile method for installing hindered quaternary centers with excellent stereocontrol.

Sulfinylnitriles: Sulfinyl–Metal Exchange–Alkylation Strategies

Adding organolithiums, Grignard reagents, or zincates to sulfinylnitriles triggers a facile sulfinyl-metal exchange to afford N- or C-metalated nitriles. Sulfinyl-magnesium exchange-alkylations efficiently install quaternary and tertiary centers, even in the case of tertiary sulfinylnitriles that contain a highly acidic methine proton. α-Sulfinylalkenenitriles afford moderately nucleophilic magnesiated nitriles, and the reactivity can be dramatically increased by conversion to the corresponding magnesiates. The sulfinyl-metal exchange is extremely fast, proceeds efficiently with quaternary, tertiary, and vinylic α-sulfinylnitriles, and exhibits an exceptional functional group tolerance in nitrile alkylations.

Cyclohexanecarbonitriles: assigning configurations at quaternary centers from (13)C NMR CN chemical shifts.

(13)C NMR chemical shifts of the nitrile carbon in cyclohexanecarbonitriles directly correlate with the configuration of the quaternary, nitrile-bearing stereocenter. Comparing (13)C NMR chemical shifts for over 200 cyclohexanecarbonitriles reveals that equatorially oriented nitriles resonate 3.3 ppm downfield, on average, from their axial counterparts. Pairs of axial/equatorial diastereomers varying only at the nitrile-bearing carbon consistently exhibit downfield shifts of delta 0.4-7.2 for the equatorial nitrile carbon, even in angularly substituted decalins and hydrindanes.