Catalytic Asymmetric Synthesis of Quaternary Barbituric Acids

Abstract

The catalytic asymmetric α-functionalization of prochiral barbituric acids, a subtype of pseudosymmetric 1,3-diamides, to yield the corresponding 5,5-disubstituted (quaternary) derivatives remains essentially unsolved. In this study 2-alkylthio-4,6-dioxopirimidines are designed as key 1,3-diamide surrogates that perform exceedingly in amine-squaramide catalyzed C-C bond forming reactions with vinyl ketones or Morita-Baylis-Hillmann-type allyl bromides as electrophiles. Mild acid hydrolysis of adducts affords barbituric acid derivatives with an in-ring quaternary carbon in unprecedented enantioselectivity, offering valuable materials for biological evaluations.

Asymmetric Synthesis of Spirocyclopentane Oxindoles Containing Four Consecutive Stereocenters and Quaternary α-Nitro Esters via Organocatalytic Enantioselective Michael–Michael Cascade Reactions

“…In addition, catalysts III and VI were also prepared according to the literature procedure. 15 Catalyst IV (CAS no: 1211565-08-0) was purchased from Sigma-Aldrich and Daicel Chiral Technologies. Catalyst VI was prepared from (+)-quinidine (CAS number 56-54-2, purchased from Alfa Aesar).…”

Enantioselective Catalytic Transformations of Barbituric Acid Derivatives

“…That is noteworthy as this requires the chiral discrimination between an NMe and NH amide moieties of the pro-nucleophilic partner 20. Recently, Palomo and co-workers tackled the enantioselective alkylation reaction of non-symmetrical barbituric acid derivatives making use of an organocatalytic strategy (Scheme 5) [31]. After the observation of very moderate ees obtained using (thio)barbituric acid nucleophiles, this research established that 2-alkylthio-4,6-dioxopyrimides 25 were competent barbituric acid surrogates for the conjugate addition reaction to vinyl aryl ketones 26.…”

“…Notwithstanding this major achievement in this field of research, the Michael reaction could not be extrapolated to less reactive acrylate derivatives, and the moderately sterically hindered acrolein led to a modest ee of 48% [31]. Nevertheless, this group showed that enone 30 (Scheme 6), a precursor of acrylates or acrolein after oxidative cleavage sequences, was able to undergo the stereoselective conjugate addition of 25 under rather similar organocatalytic conditions to give barbituric acid products 31 with ees between 81% and 94%, after an acidic hydrolysis of the 2-benzylthioether moiety.…”

“…The optimization demonstrated that the best results were obtained with electrophile 33 having a tert-butyl ester and K 2 CO 3 proved to be the more suitable base. The authors illustrated the usefulness of the obtained barbiturate derivatives, such as 34, possessing an all-carbon quaternary stereocenter by performing various transformations [31]. For instance, a metathesis reaction on product 34 furnished the cyclopentene 35 in 78% yield (Scheme 7).…”

“…Notwithstanding this major achievement in this field of research, the Michael reaction could not 209 be extrapolated to less reactive acrylate derivatives, and the moderately sterically hindered acrolein 210 led to a modest ee of 48%[31]. Nevertheless, this group showed that enone 30 (Scheme 6), a…”