Short Stereoselective Synthesis of α-Substituted γ-Lactams

Abstract

A concise, stereoselective synthesis of α-substituted γ-lactams is reported. γ-Lactam scaffolds 2 and 3 possessing an Evans' chiral auxiliary and two types of N-substituents were successfully alkylated with different electrophiles to give α-substituted γ-lactams with reasonable diastereoselectivities. The use of a masked carboxymethyl function off the lactam nitrogen provided a convergent means to α-substituted γ-lactam dipeptide isosteres.γ-Lactams, with their ψ angle constrained, are important constituents of β-turn peptidomimetics. Our ongoing research on the synthesis of unsubstituted 1,2 and substituted 3 γ-lactam peptide isosteres as Pro-Leu-Gly-NH 2 (PLG) mimics led us to reinvestigate the existing synthetic methodologies to this scaffold. Over the years, several approaches have been used for the synthesis of peptidomimetics containing lactam scaffolds. One method of obtaining the lactam is through a route established by Freidinger et al 4 , involving the formation of a sulfonium salt followed by subsequent intramolecular cyclization. Other widely used approaches are reductive amination followed by thermal cyclization 5 and an intramolecular Mitsunobu reaction. 6 For α-substituted γ-lactams, the stereoselective synthesis of α,α-dialkyl amino acids has to be achieved prior to their incorporation into the lactam by the above methods. 5,7,8 In short, the current methods for the synthesis of α-substituted γ-lactams are linear in their approach. Thus, there is a need for a more efficient and versatile approach for such syntheses.AUTHOR EMAIL ADDRESS johns022@umn.edu. SUPPORTING INFORMATION. Experimental procedures and spectral data for 2, 5, 7, 8, 11−13, and 15−18. X-ray structure data (ORTEP diagrams and CIF files) for 7a and 15a. This material is available free of charge via the Internet at http://pubs.acs.org. Recently, Palomo et al. 9 constructed α-substituted β-lactams in a stereoselective manner with template 1. We felt that such an approach could be adapted to the more commonly used γ-lactam scaffold, thereby providing a method for the stereoselective synthesis of highly desirable α-substituted γ-lactams. Such a method would greatly enhance the utility of the γ-lactam scaffold in peptidomimetic design. Since the synthetic approach used for template 1 was not deemed applicable for the γ-lactam system, compounds 2 and 3 were designed to serve as potential templates for the stereoselective synthesis of α-alkylated γ-lactams. NIH Public AccessIn 2, the 4-methoxy-benzyl moiety was incorporated as the lactam N-substituent in our initial studies because of its ready availability and its ease of removal. We recognized, however, that template 2 suffered from the same drawback as template 1 in that in order for both lactam templates to serve as useful synthetic dipeptide isosteres, the lactam N-substituent first needed to be removed and the lactam then N-alkylated with a suitable carboxymethyl derivative. We felt that the versatility of a template like 2 could be enhanced if the N-substituent was a masked...

Cu and Cu-Based Nanoparticles: Synthesis and Applications in Catalysis

“…γ-Lactams and related motifs are important components of various biologically active compounds, natural products, and pharmaceuticals, − and therefore, several effective methodologies for preparing a wide variety of γ-lactams, including α-, β-, and γ-substituted ones, have been reported. − The development of efficient C–H bond functionalization reactions that proceed under benign conditions is a major goal of current research in organic chemistry, and studies along these lines have borne impressive fruit. − Synthetic protocols allowing the cleavage of C–H bonds adjacent to nitrogen atoms under oxidative conditions in the presence of catalysts have been reported . For instance, Kantam and co-workers found that CuO NPs catalyzed the formation of N -aryl-γ-amino-γ-lactams via the oxidative coupling of aromatic amines with 2-pyrrolidinone (Figure ).…”

Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug

“…The synthesis of (±)-7 was achieved in two steps using a modification of the reported procedure for a related bromolactam. 3 Starting from acylation of benzylamine 4 with acid chloride 5, 4 bromolactam 7 as a racemic mixture. Attempts to separate the enantiomers were successful using preparative chiral supercritical fluid chromatography (SFC); however, each enantiomer quickly racemized back to (±)-7 during evaporation, thus necessitating the use of the racemic material in this, our original approach, with resolution now to occur at a later stage in the synthesis.…”

“…The initial approach for the preparation of fragment 2 targeted X = Br, and the synthesis of bromolactam (±)- 7 is shown in Scheme . The synthesis of (±)- 7 was achieved in two steps using a modification of the reported procedure for a related bromolactam . Starting from acylation of benzylamine 4 with acid chloride 5 , base-promoted cyclization then afforded bromolactam 7 as a racemic mixture.…”

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.15 (s, 4H), 4.42 (s, 2H), 4.37 (t, J = 7.6 Hz, 1H), 3.32−3.18 (m, 1H), 3.10 (dt, J = 9.7, 7.5 Hz, 1H), 2.36 (s, 3H), 2.29 (dtd, J = 12.6, 7.6, 3.1 Hz, 1H), 1.97−1.84 (m, 1H), 0.95 (s, 9H), 0.20 (d, J = 10. 3 (S)-3-Hydroxy-1-(4-methylbenzyl)pyrrolidin-2-one (21). HCl (4 M in 1,4-dioxane, 707 mL, 2828 mmol) was added in one portion to a solution of 20 (180 g, 566 mmol) in anhydrous CH 2 Cl 2 (600 mL) at room temperature maintained under a N 2 atmosphere.…”

Functionalization of N-[(Silyl)methyl]-β-lactam Carbanions with Carbon Electrophiles

“…They were reacted with N -[(silyl)methyl]-β-lactam carbanions, generated under optimized conditions, to furnish moderate to good yields of the corresponding desilylated and α‘-functionalized N -methyl-β-lactams 26 − 36 . Interestingly, the method was applicable to all the α,β-substitution and N -protection patterns studied, including monosilyl-β-lactams 14 and 17 , and some of the α- N -Boc-α‘-carboxy-β-lactams prepared (e.g., 34 − 36 ) could be considered as internally constrained peptidomimetics, ready for incorporation into peptide chains by standard peptide synthesis techniques 2 Functionalization of N -[(silyl)Methyl]-β-lactams with Carbon Dioxide and Related Electrophiles entryβ-lactamYR 1 R 2 R 3 baseelectrophile a productEyield (%) b 1 10 Xc H H Bn s BuLi (−78) CO 2 26 CO 2 H 58 2 10 Xc H H Bn s BuLi/TMEDA (−78) ClCO 2 Bn 19 77 3 10 Xc H H Bn s BuLi (−78) ClCO 2 Bn 27 CO 2 Bn 45 4 10 Xc H H Bn n BuLi/TMEDA (−100) PhNCO 28 CONHPh 63 5 11 Xc H H i Bn n BuLi/TMEDA (−100) CO 2 29 CO 2 H 90 6 11 Xc H H i Bn n BuLi/TMEDA (−100) Me 3 SiNCO 30 CN 60 7 11 Xc H H i Bn n BuLi/TMEDA (−100) Me 3 SiNCO c 31 CONH 2 80 8 12 Xc H Ph Bn n BuLi/TMEDA (−100) PhNCO 32 CONHPh 74 9 14 Xc i Bn H …”