An efficient multi-component synthesis of N-1-alkylated 5-nitrouracils from α-amino acids

Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne

“…For analogs bearing a quaternary C centers at N-1, we were obliged to develop a novel 3MCR (multicomponent reaction) to prepare the gem -dimethyl and cyclopropyl analogs (Scheme ). Briefly, aminocarbonylation of the amino acid residues followed by protection of the carboxylic acid residue afforded primary urea precursors 26 . Condensation of 26 with ethyl nitroacetate in the presence of triethyl orthoformate afforded a 6:4 E / Z ratio of ene-urea intermediates 27 .…”

“…The crude product was purified by flash chromatography (silica gel, gradient of 0−100% EtOAc in heptane) to afford 1-{3-isopropyl-5- [2-methyl-4-(naphthalen-2-ylamino) 7.51 (d,J = 8.4 Hz,1H),7.42 (ddd,J = 8.2,6.8,1.4 Hz,1H),2H),2H),5.85 (ddt,J = 17.3,10.7,4.8 Hz,1H),2H),4.77 (h,J = 6.7 Hz,1H),2H),2.43 (s,3H), 1.84−1.64 (m, 2H), 1.55−1.20 (m, 8H); 13 C NMR (DMSO-d 6 ) δ 170. 24, 159.94, 149.89, 145.30, 140.18, 138.35, 134.26, 132.27, 131.18, 129.61, 128.98, 128.70, 127.50, 126.50, 126.40, 126.19, 123.44, 120.58, 118.16, 116.88, 113.03, 112.76, 111.48, 65.04, 54.95, 48.38, 35.67, 20.93, 20.58, 19.48, 19.22 (44). A stirred solution of 43 (840 mg, 1.52 mmol, 1.00 equiv), 1,3-dimethylbarbituric acid (380 mg, 2.43 mmol, 1.60 equiv) in DCM (42 mL) was degassed and purged with nitrogen, and tetrakis(triphenylphosphine)palladium(0) (70.3 mg, 0.06 mmol, 0.04 equiv) was added.…”

Synthesis and stability evaluation of novel peptidomimetic Caspase-1 inhibitors for topical application

“…To overcome this stability issue of the piperidin-2,6-dione series, we decided to transpose our SAR to a 1,3,5-trisubstituted uracil scaffold [7,11]. We anticipated that the stability issues would be addressed by preventing ring opening and replacing the sensitive chiral center at C3-H of the piperidin-2,6-dione unit that we had great difficulty in controlling during the assembly of our final products (eg., 1 and 14) [8].…”

Trisubstituted push-pull nitro alkenes

“…Second method B can be considered as an analog to method A for the preparation of 3-amino-substituted reviewed structures. 14,28,[34][35][36][37][38] The products 3-alkylamino-2-nitroacrylic esters used to be prepared by nucleophilic vinylic substitution on 3-alkoxy-2-nitroacrylic esters with adequate N-nucleophile. 28 The paper 31 describing reactions with diverse groups of N-nucleophiles and utilizing "one-pot" reaction pathway B depicted in (Scheme 3), was published in 1963.…”

“…The first group contains mostly pyrimidine or pyrimidone derivatives (Scheme 9) that are formed by reactions with ureas and amidines. [13][14][15]18,31,34,59,60 There are also examples of other six-membered heterocycles (pyridine 35 and thiadiazine 61 ) prepared in a similar manner. The second group contains structurally more different products (Scheme 10) that are formed by reaction with usually amino heterocycles as 1,3-binucleophiles.…”