Bifunctional Brønsted Base Catalyzes Direct Asymmetric Aldol Reaction of α‐Keto Amides

Abstract

The first enantioselective direct cross-aldol reaction of α-keto amides with aldehydes, mediated by a bifunctional ureidopeptide-based Brønsted base catalyst, is described. The appropriate combination of a tertiary amine base and an aminal, and urea hydrogen-bond donor groups in the catalyst structure promoted the exclusive generation of the α-keto amide enolate which reacted with either non-enolizable or enolizable aldehydes to produce highly enantioenriched polyoxygenated aldol adducts without side-products resulting from dehydration, α-keto amide self-condensation, aldehyde enolization, and isotetronic acid formation.

Bifunctional Brønsted Base Catalyzed Mannich Reaction of β‐Alkoxy α‐Keto Amides: Stereocontrolled Entry to Functionalized Amino Diols

“…Trying to fill this gap, we have recently described the first direct enantioselectivec ross-aldol reaction of b-alkoxy a-keto amides with aldehydes catalyzed by ab ifunctionalB rønsted base (Scheme 1b). [10] We now document the first direct Mannich-typer eactiono ft hese b-alkoxy a-keto amides, which further provest heir utility as efficient pronucleophile partners and provides ar oute to highly versatile enantioenriched amino polyols.…”

“…Most examples employ piruvates and belong to the Michael type reaction, for which metallo‐ and organocatalytic approaches have been described, whereas the aldol and Mannich‐type reactions have been scarcely examined. Trying to fill this gap, we have recently described the first direct enantioselective cross‐aldol reaction of β‐alkoxy α‐keto amides with aldehydes catalyzed by a bifunctional Brønsted base (Scheme b) . We now document the first direct Mannich‐type reaction of these β‐alkoxy α‐keto amides, which further proves their utility as efficient pronucleophile partners and provides a route to highly versatile enantioenriched amino polyols.…”

“…The experiments soon revealed nosyl protected imines to be the most suitable azometines for this Mannich reaction. Nevertheless, to our disappointment, ureidopeptide‐based Brønsted base catalysts, which were the most effective in promoting the parent stereoselective aldol reaction, displayed poor control over the reaction selectivity; the addition of either α‐ketoamide 1 a or 1 b to nosyl imines, promoted by catalysts C1 and C2 , afforded the corresponding Mannich adducts in generally good conversion and high diastereoselectivity but poor enantioselectivities regardless of the reaction temperature (Table , entries 5–8). Likewise, the thiourea catalysts C3 and C4 provided poor enantiocontrol in the reaction of 1 a with imine 7 a (entries 9, 10).…”

Bifunctional Brønsted Base Catalyzes Direct Asymmetric Aldol Reaction of α‐Keto Amides

“…Ther elative and absolute configurations of the major syn,syn enantiomer were determined by X-ray crystallographic analysis of 4Bd (Scheme 2a)a nd auniform reaction mechanism for the aldol reaction was assumed. [20] Taking into account the diastereo-and enantioselectivity observed, the capacity of the ureidopeptide-based catalysts to mainly produce syn-configured adducts might be consistent with the generation, as ar esult of electrostatic and hydrogenbonding interactions,o famore stabilized Z enolate which preferentially approaches the Si face of the aldehyde (Scheme 2b). Although we still have no evidence of the actual mode of substrate-catalyst interaction, [21] the fact that reactions with common Brønsted base catalysts,aswell as with C7, were significantly less efficient supports the beneficial effect of multiple hydrogen-bonding interactions to boost reactivity.…”

N,N‐Diacylaminals as Emerging Tools in Synthesis: From Peptidomimetics to Asymmetric Catalysis

“…Ap articularly challenging transformations uch as the Brønsted base-catalyzed cross-aldol reaction also demonstrated the beneficial effect of the aminal-urea pairt ob oost reactivity and ensure stereoselectivity.T he direct reaction of a-keto amides with enolizable, as well as non-enolizable aldehydes, was accomplished thanks to the action of aCbz-protected ureidopeptide-based Brønsted base catalyst (Scheme 16). [51] Multiple hydrogen-bonding interactions appeared to be crucial aso ther common Brønsted base catalysts were significantly less efficient. The reactionp rovided stereodefined syn aldol adducts, which were transformed into highly enantioenriched triols after reduction.T he stereoselectivity observed was rationalized by the capacity of the catalystt og enerateamore stabilized Z enolate to mainly produce syn-configured adducts (Scheme 16).…”