Asymmetric Total Synthesis of an Important 3-(Hydroxymethyl)carbacephalosporin

Abstract

Carbacephalosporins have gained much attention as important antibacterial agents. Recently, 3-(hydroxymethyl)carbacephalosporins have been linked to quinolones for the production of multifunctional antibiotics. A short, practical asymmetric total synthesis of carbacephalosporin 3, suitable for conjugating to other chemical moieties, is reported. The synthesis was achieved by Mitsunobu cyclization of dipeptide 12, prepared from l-erythro-anti-β-hydroxy-α-amino acid 11, and subsequent Horner−Wadsworth−Emmons cyclization of ketone 16.

The Mitsunobu reaction in the chemistry of nitrogen-containing heterocyclic compounds. The formation of heterocyclic systems (review)

“…An effective method, similar to that used for the production of the β-and γ-lactams [33,42], was proposed for the synthesis of N-arylpiperazinones (Table 9) [65]. Despite the presence of an unprocted amino group in the structure of the precursors of the N-arylpiperazinones (the amido alcohols 76) the formation of the corresponding aziridines was not observed.…”

“…This heterocyclic fragment enters the structure of a wide range of antibiotics such as penicillins, cephalosporins, carbapenemes, and monobactams [33][34][35]. The Mitsunobu reaction can serve as a convenient method for the synthesis of β-lactams [33][34][35][36][37].…”

“…A significant advantage of amide substrates is their increased NH acidity, and the introduction of additional activating groups is not necessary for successful cyclization under the conditions of the Mitsunobu reaction. Closure of the β-lactam ring under Mitsunobu conditions was used in the synthesis of the carbacephalosporin 23 [33].…”

Inhibitors of HCV NS5B polymerase. Part 2: Evaluation of the northern region of (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid

“…As shown in Scheme 2, the loading precursor was prepared from tert-butyl P,P-dimethylphosphonoacetate 10 by treatment with O-(diphenyl phosphinyl)hydroxylamine 6 in the presence of NaH to affect a-amination. 7 The resulting amine 11 was protected as its FMOC derivative 12 and the tert-butyl ester hydrolyzed with TFA to provide carboxylic acid 13 suitable for loading onto solid support. In that event, a mixture of carboxylic acid 13 and Wang resin was treated with DIC and catalytic DMAP for 12 h. After the coupling reaction, any unreacted loading sites were derivatized with acetic anhydride.…”

α-Amino acid derivatives with a Cα-P bond in organic synthesis

“…28 Benzyl diethoxyphosphorylacetate (25, R = PhCH 2 ) was aminated with this reagent in THF at -78 o C in the presence of sodium hydride, obtaining the amination product 3a in 60-74% yields. [28][29][30] Electrophilic amination of the α-position of diethoxyphosphorylacetates can also be performed in a few steps, e.g. by the reaction of the enolate anion derived from the ester 25 with ethyl nitrite, followed by the reduction of the obtained oxime 26 with zinc in acetic acid or aluminum amalgam (Scheme 11).…”