Asymmetric Carbon–Carbon Bond Formation via N-Amino Cyclic Carbamate (ACC) Hydrazones



Journal Title

Journal ISSN

Volume Title



Formation of carbon–carbon bonds is a fundamental transformation in synthetic organic chemistry. α-Alkylation of carbonyl compounds via electrophilic addition to enolates is one of the various methods used in constructing these bonds. Over the years, the field has undergone significant advancement and highly selective asymmetric methods are now available for the α-alkylation of carbonyl compounds. Recently, our group introduced the N‑amino cyclic carbamate (ACC) chiral auxiliaries for asymmetric α-alkylation of ketone. The ACC auxiliaries are both easily introduced into and removed from ketones, with near quantitative recovery of the auxiliary. Furthermore, deprotonation of the hydrazones is rapid and regioselective, and alkylation does not require extreme low temperature, yet it proceeds with excellent stereoselectivity and consistently high yields. In what follows, we describe several projects in method development utilizing the ACC auxiliaries. An easy and convenient method to access the ACC auxiliaries via direct N-amination of oxazolidinones has been developed using a combination of t-BuOK and monochloramine (NH2Cl). Not only was the NH2Cl used in this method atom economical, but given that it is readily accessible from commercial bleach, it is also convenient and inexpensive. A detailed mechanistic study on the ACC hydrazone alkylation was conducted using seven ACC auxiliaries and 3-pentanone. In this study, the regio- and stereoselectivity of the alkylation were determined at the level of both the ACC hydrazones and the hydrolyzed ketones. The ACC auxiliaries also have been utilized for the first α,α-bisalkylation of various chiral, nonracemic methyl ketones and observed a matched/mismatched pairing between the existing chiral center on the ketones and auxiliaries. In the matched case high diastereoselectivity and in the mismatched case diminished diastereoselectivity was observed. Finally, a mechanistic investigation was conducted on a highly regio- and stereoselective anti-aldol process we developed recently. With experimental data and theoretical calculations, we concluded that at low temperature it favors the syn-aldol product but at higher temperature the syn-aldolate converts to anti-aldolate via a reversible thermodynamic process.



Α-alkylation, Stereoselectivity