Enantioselective Synthesis of Chiral Substituted 2,4-Diketoimidazolidines and 2,5-Diketopiperazines via Asymmetric Hydrogenation

Abstract

An enantioselective hydrogenation of 5-alkylidene-2,4-diketoimidazolidines (hydantoins) and 3-alkylidene-2,5-ketopiperazines catalyzed by the Rh/f-spiroPhos complex under mild conditions has been developed, which provides an efficient approach to the highly enantioselective synthesis of chiral hydantoins and 2,5-ketopiperazine derivatives with high enantioselectivities up to 99.9% ee.

Phase-Transfer-Catalyzed Alkylation of Hydantoins

“…After developing a robust alkylation protocol, we sought to develop an asymmetric version of our reaction (Figure D). Indeed, to date, there are only a hand full of asymmetric transformations that allow us to control the stereochemistry at the C5 position of a hydantoin; these include the enantioselective hydrogenation catalyzed by chiral rhodium complexes, the diastereoselective aldol using aldehydo sugars, the asymmetric Friedel-Craft alkylation catalyzed by chiral phosphoric acids, and the photochemical deracemization of C5-substituted hydantoins through a reversible hydrogen atom transfer . Besides the aforementioned methods that allow a direct functionalization of hydantoins, there are also several asymmetric syntheses of hydantoins reported in the literature, but they mainly rely on the preinstallation of the chirality prior to the formation of the ring. − Asymmetric phase-transfer catalysis has become a prominent part of organocatalysis with some fantastic examples reported by Maruoka, Denmark, Itsuno, Kitamura, Park, Andrus, Itoh, Arai, and others. , For our part, we sought to induce enantioselectivity by replacing TBAB with a chiral phase-transfer catalyst such as PTC-1 , which was initially developed by Maruoka and co-workers and proved successful in numerous asymmetric alkylation reactions.…”

“…After developing a robust alkylation protocol, we sought to develop an asymmetric version of our reaction ( Figure 4 D). Indeed, to date, there are only a hand full of asymmetric transformations that allow us to control the stereochemistry at the C5 position of a hydantoin; these include the enantioselective hydrogenation catalyzed by chiral rhodium complexes, 16 the diastereoselective aldol using aldehydo sugars, 31 the asymmetric Friedel-Craft alkylation catalyzed by chiral phosphoric acids, 32 and the photochemical deracemization of C5-substituted hydantoins through a reversible hydrogen atom transfer. 33 Besides the aforementioned methods that allow a direct functionalization of hydantoins, there are also several asymmetric syntheses of hydantoins reported in the literature, but they mainly rely on the preinstallation of the chirality prior to the formation of the ring.…”

“…Given the significance of this particular heterocycle, numerous effective methods have been developed over the years to access this heterocycle, such as the Bucherer–Bergs, Biltz, and Urech syntheses . However, methods that allow a direct and selective C-functionalization of preformed hydantoins are still somewhat scarce. − Indeed, the current approaches to the desired C-alkylated products typically involve either a two-step protocol featuring aldol condensation followed by reduction/hydrogenation with the possibility of running the reduction in an asymmetric fashion (Figure A) , or direct alkylation that usually requires the use of a strong base (e.g., LiHMDS) and/or cryogenic conditions (Figure B) . Several examples also involve the highly hazardous combination of NaH and DMF to facilitate alkylation, , while the use of transition metals in conjunction with strong bases has been reported to catalyze selective C-arylations (Figure C) .…”

Chiral 1,2,3‐Triazolium Salt Catalyzed Asymmetric Mono‐ and Dialkylation of 2,5‐Diketopiperazines with the Construction of Tetrasubstituted Carbon Centers

“…Given their unique functions in the agriculture, chemical, food, medicinal, and material fields, along with their structural diversity which associated with synthetic challenges, the asymmetric syntheses of DKP motifs have attracted the attention of organic synthetic and biosynthetic chemists [8, 9] . In addition to classical condensation cyclization of chiral linear dipeptide precursors [8a,b] and other chiral substrate‐induced transformations, [8c–k, 9] a few catalytic asymmetric reactions have been developed for constructing DKP moieties, including Pd‐catalyzed allylations, [10a] Michael additions, [10b,c] α ‐sulfenylations, [10d] and asymmetric dehydrogenations [10e,f] . However, these synthetic methods have been used to access DKP motifs devoid of tetrasubstituted carbon centers or bearing only one such center.…”

Diastereoselective Spirocyclization: Entry to Spirocyclic Diketopiperazines

“…DKPs are cyclic dipeptide moieties featuring a well-defined geometry and resemblance to protein secondary structures and exhibiting diverse biological and pharmacological activities. − Substituents can be introduced on this motif at the two stereocenters as well as on the amide nitrogen atoms. , When DKPs are fused with another cyclic structure, a spirocyclic framework can be formed that could be utilized as a novel chemotype in drug discovery . The conventional approach to accessing 2,5-diketopiperazine involves sequential amide bond formations to forge the two amino acids and form the cyclic dipeptides. ,,− Alternatively, diastereoselective and catalytic asymmetric methodologies have provided robust approaches to access chiral diketopiperazines from achiral substrates. − Our approach to access 2,5-diketopiperazine-containing spirocyclic compounds proceeds through an orthogonal disconnection strategy (Scheme b).…”