Divergent Synthesis of γ‐Amino Acid and γ‐Lactam Derivatives from meso‐Glutaric Anhydrides

Abstract

The first divergents ynthesis of both g-amino acid and g-lactam derivativesf rom meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN 3 relies on controlled generation of an ucleophilic ammoniuma zide species mediated by ap olystyrene-bound base to promote efficients ilylazidation. After Curtiusr earrangemento ft he acyl azide intermediatet o access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformlyh igh yields of g-aminoa cids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation-cyclisation cascade in situ to provide synthetically useful yields of g-lactamd erivatives without using anyf urther activating agents. Mechanistic insights invoke the intermediacy of an unconventional g-N-carboxyanhydride (g-NCA) in the latter process. Among the examples prepared using this transformation are 8APIs/moleculeso f considerable medicinali nterest.

Preparation of Lactams from Cyclic Anhydrides via N‐Carboxyanhydride Intermediates

“…no external activating agent, CO 2 as the only by‐product), its application is limited to reactions between sterically‐hindered carboxylic acids and electron‐deficient isocyanates, in the main due to the formation of acid anhydride‐, urea‐ and N ‐acylurea‐based side products derived from the NCA intermediate. By contrast, we have shown [4] the relatively unexplored utilisation of the methodology in an intramolecular setting supresses competing intermolecular side‐reactions under high‐dilution conditions.…”

“…Recently, our group reported the first divergent strategy to prepare both γ‐amino acids and γ‐lactams from a common intermediate derived from the reaction of meso ‐glutaric anhydrides with TMSN 3 [4] . These anhydrides, in the presence of a catalytic amount of a polystyrene‐bound analogue of Hünig's base (DIPEA@PS), underwent an efficient desymmetrisation reaction with TMSN 3 to give acyl azides.…”

“…[3] Recently, our group reported the first divergent strategy to prepare both γ-amino acids and γ-lactams from a common intermediate derived from the reaction of meso-glutaric anhydrides with TMSN 3 . [4] These anhydrides, in the presence of a catalytic amount of a polystyrene-bound analogue of Hünig's base (DIPEA@PS), underwent an efficient desymmetrisation reaction with TMSN 3 to give acyl azides. Utilising a thermal Curtius rearrangement, the crux of the strategy relies on the smooth generation of an isocyanate in the presence of a tethered carboxylic acid (intermediate 2, Figure 1C); a challenging motif to prepare by other means due to a competing intermolecular oligomerisations initiated by either nucleophiles or bases.…”

Fluoride Additive as a Simple Tool to Qualitatively Improve Performance of Nickel-Catalyzed Asymmetric Michael Addition of Malonates to Nitroolefins

“…13 C {1H} NMR (101 MHz, D 2 O): δ 175.4, 138.4, 135.1, 129.8, 127.7, 43.7, 39.4, 38.2, 20.0. NMR spectra are in agreement with the literature data …”

“…NMR spectra are in agreement with the literature data. 63 (S)-3-Carboxy-2-(p-tolyl)propan-1-aminium Chloride (2f). Purified product 1j (100 mg, 0.339 mmol, 1 equiv) was dissolved in EtOH (2 mL), and this solution was placed in a 250 mL Schlenk tube; then, 3.6 mg of Pd/C (10 wt %, 1 mol %) was added under an Ar atmosphere.…”