Synthesis of a natural product-inspired eight-membered ring lactam library via ring-closing metathesis

Abstract

We have prepared a novel speculative eight-membered lactam demonstration library based on the skeletal structure of the potent antitumor marine natural product octalactin A. The basic scaffold was readily constructed in a convergent fashion via ring-closing metathesis chemistry from the corresponding diene amides. A cursory examination of the biological properties of the library validates the relevance and significance of these structures. KeywordsEight-membered; Natural product; Lactam; Library; Ring-closing metathesis; Medium-ring; Octalactin; Parallel synthesis Libraries of compounds based on natural products have gained in importance in recent years. 1,2 Although the structures contained in these libraries tend to be fairly diverse, one class of compound remains to be fully exploited, namely, the monocyclic medium-ring. 3,4 An interesting natural product from the standpoint of structural architecture and biological profile is the powerful antitumor marine natural product octalactin A, 1 (Fig. 1). 5,6 This fascinating natural product which features a rare saturated eight-membered lactone core continues to receive considerable attention in total synthesis efforts from many laboratories. 7 We have previously constructed this lactone by means of an especially facile and direct lactonization from the corresponding seco acid ('zip-up' approach), 7a,8 and by an equally facile ring-closing metathesis (RCM) route ('zip-down' approach) to afford the unsaturated oxocene. 9 These enabling technologies prompted us to investigate the feasibility of generating a speculative eight-membered ring library inspired by octalactin A.In order to simplify the synthesis, we elected in the present work to construct a simpler lactam scaffold that at a minimum retained the eight-membered core feature of the octalactins. The strategy is depicted in Scheme 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe unsaturated lactam scaffold 2 would be constructed by means of RCM. The diene amides 3 would result from the condensation of the racemic Fmoc-protected 3-amino-5-hexenoic acid 4 and the sublibrary of various racemic secondary allylic amines 5. The allylic amines in turn would be derived from vinyl Grignard addition to the Schiff bases. By using readily prepared racemic components, a mixture of diastereomers 2 would be obtained resulting in a larger library with a relative minimum of effort and cost. Separation of the diastereomeric scaffolds would precede derivitization of the primary amines, thus generating the desired lactam library.The allylic amine sublibrary was prepared as shown in Scheme 2. Reaction of a series of commercially available benzaldehydes 6a-h and benzyl amines 7a-f in ether at room temperature in the presence of magnesium sulfate 10 gave after filtration the Schiff bases in nearly quantitative yield in all cases.Addition of vinyl Grignard with BF 3 ·OEt 2 at −78 °C for 12 h gave a representative 13-member sublibrary in 67−87% yield (Fig. 2).Synthesis of the racemic Fmoc-protect...

Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins

“…The chemical syntheses and structures of most of these novel compounds have already been published or will be reported in detail elsewhere (3,4). This study was initiated after we discovered that spectrophotometric time scans demonstrated the ability of 4–25 μ M concentrations of DL-II-D7 to increasingly mimic the inhibitory activity of 41–256 nM concentrations of pravastatin on the catalytic domain of purified HMG-CoA reductase in a cell-free assay in vitro (Fig.…”

“…The synthesis of the 10-member sublibrary of novel unsaturated eight-membered lactam compounds used in this study (DL-II-D4 and DL-II-D7; GG-II-Ala29, GG-II-G3-cis, and GG-II-G7; NB-IX-Gly27, NB-IX-Gly35, NB-IX-Gly38, NB-IX-Gly44 and NB-IX-Gly46) was performed in the convergent-divergent manner described previously (3,4). In general, ring-closing metathesis (RCM) of a collection of diene amides (prepared from the carboxylic acids and the fluorinated secondary allyl amine), was followed, after deprotection, by parallel derivatization of the resulting cyclic secondary amine scaffold (Scheme 1).…”

“…But this compound inhibited the polymerization of purified tubulin, suggesting that microtubule de-stabilization might be involved in its cytostatic action (2). Pilot-scale libraries of 2nd and 3rd generation 8-membered medium-ring lactams (MRLs) inspired by octalactin A were then synthesized for optimization studies and screened for bioactivity in hyperplastic tumor cell systems in vitro (3,4). Several MRLs inhibited, in a concentration- and time-dependent manner, tumor cell proliferation in the low μ M range after 2 and 4 days in culture and were effective across a spectrum of leukemic (L1210 and HL-60), pancreatic (Pan02) and mammary (SK-BR-3) tumor cell lines.…”

Electrochemical Ring Expansion to Synthesize Medium-Sized Lactams Through C–C Bond Cleavage

“…On the other hand, no product was detected without the addition of NaOAc and a large amount of the substrate remained (Table 1 After obtaining optimized reaction conditions, we first evaluated the effect of substituents on the aniline moiety (Figure 2). Anilines bearing substituents like fluoride, chloride, or no substituent at the para-position showed good reactivity in the synthesis of nine-membered lactams (2)(3)(4). Notably, the electron-rich amides, which failed previously, 22 were now suitable under the current conditions.…”

“…Medium-sized lactams are prevalent structural motifs found in a variety of natural products and medicinal compounds. [1][2][3][4][5][6] Owing to unfavorable enthalpic and entropic barriers during the transition states of forming medium-sized rings, access to these molecules is challenging. Conventionally, direct intramolecular head-totail cyclization strategies suffer from requirements of high-dilution solvents and competing intermolecular reactions.…”