Simple Access to Highly Functional Bicyclic γ‐ and δ‐Lactams: Origins of Chirality Transfer to Contiguous Tertiary/Quaternary Stereocenters Assessed by DFT

Abstract

This paper describes the synthesis of both polysubstituted oxazolo-pyrrolidinones and -piperidinones by a domino process. The methodology is based on the reaction between hydroxyl halogenoamides and Michael acceptors, which leads efficiently to bicyclic lactams. The process is compatible with unsymmetrical electron-withdrawing groups on the Michael acceptor, which allows the formation of two contiguous and fully controlled tertiary and quaternary stereocenters. In the case of tetrasubstituted Michael acceptors, two adjacent quaternary stereocenters are formed in good yield. Starting from (R)-phenylglycinol derived amides results in the formation of enantioenriched bicyclic lactams in low to good yields and with high levels of stereoselectivity, thus greatly increasing the scope and interest of this strategy. The origins of chirality transfer and diastereoselectivity were studied by DFT calculations and have been attributed to a kinetic control in one of the last two steps of the reaction sequence. This selectivity is dependent upon both the substituents on the Michael acceptor and the sodium cation chelation.

Acyclic Twisted Amides

“…Similar to β-lactams, the amide bond geometry of structurally characterized amides embedded in a fused five-membered ring system (Figures –) − ,− can be characterized as N-pyramidalized (average χ N of 45.9°) with minimal twist (average τ of 11.7°). As expected, the average values of N-pyramidalization and twist are slightly lower as compared to β-lactams ...…”

“…Most common in this class (Figures –) − ,− is ring fusion to six-membered rings in a [ 3 .4.0] scaffold, including piperazine, such as 4.120 , and hexahydropyrimidine, such as 4.121 , and much more common [ 3 .3.0] ring system with the ring fusion to five-membered rings, including pyrrolidine, such as 4.122 , thiazolidine, such as 4.123 ,…”

Structure-based design, synthesis, and biological evaluation of novel piperine–resveratrol hybrids as antiproliferative agents targeting SIRT-2

“…The olefenic and aromatic carbons appeared at their expected chemical shis. [36][37][38] Interestingly, the prepared compounds are soluble in common organic solvents, such as CHCl 3 , tetrahydrofuran, and Et 2 O, and partially soluble in methanol and ethanol. Compounds 5a-f easily yielded X-ray quality crystals from slow evaporation of a mixture solution of methanol and CH 2 Cl 2 with the appropriate amount of 5a-f at room temperature.…”

The Fascinating Chemistry of α‐Haloamides

“…The 1,2‐dipolar properties displayed by ethoxymethylene malonate derivatives in the domino aza‐MIRC reaction could be efficiently exploited to achieve the one‐pot synthesis of Meyers bicyclic lactams (Scheme ) –. Precisely, polysubstituted oxazolo‐pyrrolidinones C were efficiently obtained allowing Michael components B to react with α‐bromoamido alcohols A in water‐free conditions and in the presence of NaH or K 2 CO 3 .…”