Bispalladacycle‐Catalyzed Michael Addition of In Situ Formed Azlactones to Enones

Abstract

The development and further evolution of the first catalytic asymmetric conjugate additions of azlactones as activated amino acid derivatives to enones is described. Whereas the first-generation approach started from isolated azlactones, in the second-generation approach the azlactones could be generated in situ starting from racemic N-benzoylated amino acids. The third evolution stage could make use of racemic unprotected α-amino acids to directly form highly enantioenriched and diastereomerically pure masked quaternary amino acid products bearing an additional tertiary stereocenter. The step-economic transformations were accomplished by cooperative activation by using a robust planar chiral bis-Pd catalyst, a Brønsted acid (HOAc or BzOH; Ac=acetyl, Bz=benzoyl), and a Brønsted base (NaOAc). In particular the second- and third-generation approaches provide a rapid and divergent access to biologically interesting unnatural quaternary amino acid derivatives from inexpensive bulk chemicals. In that way highly enantioenriched acyclic α-amino acids, α-alkyl proline, and α-alkyl pyroglutamic acid derivatives could be prepared in diastereomerically pure form. In addition, a unique way is presented to prepare diastereomerically pure bicyclic dipeptides in just two steps from unprotected tertiary α-amino acids.

Catalytic Asymmetric Synthesis of Spirocyclic Azlactones by a Double Michael‐Addition Approach

“…The facial differentiation of the Michael acceptor moieties is thus different for enones and dienones. In our previous studies with enones, we have explained the preference for the R configuration at the β‐position to the keto group of product ( R , R )‐ 8 by coordination of the carbonyl moiety of the enone in the assumed catalytic intermediate 7 (Scheme ), whereas the S configuration in the β‐position to the keto group of product ( R , S )‐ 8 would have been expected by face‐selective olefin coordination in 9 13c…”

“…Moreover, the product was formed with only low‐to‐moderate enantioselectivity with monopalladacycles. We have explained the preference for a bimetallic catalyst by a simultaneous activation of the enone substrate and the azlactone through a bimetallic coordination mode 13c,d. To clarify if an intramolecular bimetallic activation mode is also likely in the title reaction with divinylketones, control experiments have been performed with monopalladacycles 5 and 6 (Scheme ), which are structurally related to [FBIPCl] 2 30.…”

Kooperative Katalyse mit Übergangsmetallen

“…Das Produkt bildete sich spontan mit dem Katalysator (7), wobei ein entsprechendes monometallisches Derivat weitaus geringere Anfangsreaktionsraten aufwies. (7) hat sich auch in der asymmetrischen Katalyse bewährt, um C‐H‐azide Verbindungen an Michael‐Akzeptoren zu addieren 4…”

Organocatalyzed Asymmetric 1,4‐Addition of Azlactones to α,β‐Unsaturated Trichloromethyl Ketones: Synthesis of α,α‐Disubstituted α‐Amino Acid Derivatives

“…Peters and co‐workers7b,7c,7e reported very elegant Michael additions of azlactones to enones with a mono‐ or bispalladiumcycle catalyst, and excellent results were obtained [Scheme , Equation (1)]. Thereafter, the Amarante group7a developed a (±)‐camphorsulfonic acid catalyzed protocol for this transformation with high diastereoselectivity [Scheme , Equation (2)].…”