Chemistry and Biochemistry
Bayer School of Natural and Environmental Sciences
Fraser F. Fleming
Bruce D. Beaver
David W. Seybert
Paul R. Carlier
Alkylations, Annulations, Nitriles, Stereoselective
N-metallated nitriles are fundamental intermediate that have been used to generate new C-C bonds for over a century. C-metallated nitriles are new but equally important intermediates in being able to deliver complementary stereoselectivity. C-magnesiated nitriles are directly generated from chelation-controlled conjugated addition and can successfully furnish complete stereocontrol during installation of three new stereocenters (Section II-1).
The recent development of chiral organometallics has identified a remarkable series of electrophile-dependent alkylations that are significantly impacting organic synthesis. C-magnesiated nitriles from chelation-controlled conjugated addition are chiral nucleophiles that alkylate an array of electrophiles with retentive or invertive alkylation depending on the electrophiles. Specifically, alkyl halides and most carbonyl electrophiles afford one stereoisomer with the stereochemical assignments being confirmed by X-ray diffraction (Section II-2).
Multi-component reactions rapidly assemble complex targets. Sequential 1, 2 addition and chelation-controlled conjugate addition to oxonitriles efficiently generates highly substituted cyclic nitriles. ω-Haloalkyl Grignards trigger the same sequence with intramolecular alkylation to afford octalins, hydrindanes and decalins ideally suited for terpanoid synthesis. A complementary multicoponent addition-Friedel-Crafts alkylation has been employed for the total synthesis of epi-dehydroabietic acid (Section II-3).
The exchange of á-halonitriles with i-PrMgBr directly generates C-magnesiated nitriles. The rapid exchange allows in situ alkylations with aldehyde, ketone and acyl cyanide electrophiles without prior Grignard addition (Section II-4). Furthermore the exchange uses rapid equilibration allowing the diastereoselective alkylation of diastereomeric á-bromonitriles.
Zhang, Z. (2004). Unsaturated Nitriles: Stereoselective Annulations and Alkylations (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1408