Nitriles: New Reactions and Reactivities

1. Transmissive Olefinations (J. Org. Chem. 2012, 77, 3651–3657.)

Building on our recent transmissive olefination method (Eur. J. Org. Chem. 2011, 6843) a series of morinol-type lignans were rapidly assembled using a Grignard-based transmissive olefination. In combination with palladium-catalyzed arylations, the strategy provides stereoselective access to a series of morinol olefin diastereomers and the (7Z, 8'E) and (7E, 8'E) conjugated analogs. Critical for the E/Z–stereoselectivity is a new, general method for converting alkenenitriles to alkenemethanols that circumvents the enal E/Z isomerization commonly encountered during conventional i-Bu₂AlH reduction.

2. Diastereoselective Arylations with TMPZnCl•LiCl (J. Org. Chem. 2012, 77, ASAP.)

Deprotonating substituted cyclohexanecarbonitriles with TMPZnCl•LiCl affords zincated nitriles that diastereoselectively couple with aryl bromides in the presence of catalytic Pd(OAc)₂ and S–Phos. Steric and electronic effects influence the diastereoselectivity: 4–t–butyl–, 4–TBSO–, and 2–Me–cyclohexanecarbonitriles exert virtually complete diastereocontrol whereas modest diastereoselectivity is observed with 4–i–Pr–, 4–Me– and 3–Me–cyclohexanecarbonitriles. The unusual diastereoselectivity trends should prove useful for synthesizing substituted cyclohexanecarbonitrile–containing pharmaceuticals.

3. Nitrile Alkylations through Sulfinyl–Metal Exchange (Angew. Chem., Int. Ed. 2011, 50,11790–11793)

Sequential alkylation and sulfinyl–metal exchange allows phenylsulfinylacetonitrile to function as an acetonitrile trianion equivalent. The metalated nitriles alkylate a range of electrophiles to install a diverse array of quaternary stereocenters typical of those found in nitrile–containing pharmaceuticals. The sulfinyl–metal exchange has a high functional group tolerance ideally suited for complex settings.

4. S_Ni' Displacements With Main Group Organometallics (Tetrahedron 2012, 68,2925–2942)

Strategic S_Ni' displacements feature in numerous natural product syntheses because the cyclizations are predictable and highly selective. Insightful mechanistic investigations demonstrate that syn S_Ni' displacements are favored over anti S_Ni'displacements. Highly enantio–and diastereoselective cyclizations are directed by chiral centers inside or outside the forming ring – even when the only chiral center is at the leaving group! The combination of high stereocontrol, facile entry to diverse ring sizes, and predictable diastereoselectivity are stressed in this review that highlights the fundamental stereocontrol necessary for the continued development of S_Ni' reactions in strategic cyclizations.

5. Nitrile-Containing Pharmaceuticals: (J. Med. Chem. 2010, 53,7902–7917)

Structurally diverse nitrile–containing drugs are in use for a variety of medical treatments. These range from blockbuster drugs such as anastrazole to numerous candidates currently being pursued in clinical trials. Surveying the interactions of the nitrile within these pharmaceuticals and drug candidates reveals that the biological function of the nitrile group varies considerably. In some instances the nitrile merely polarizes the adjacent electron density whereas in other cases the nitrile is a key component for molecular recognition. We recently reviewed the roles of the nitrile pharmacophore in over 30 nitrile-containing pharmaceuticals and more than 20 additional nitrile-containing leads in clinical development.