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Discovery of novel β-lactam analogs oriented to control multidrug-resistant bacteria enabled by Pd-catalyzed C–H activation of aliphatic amines

Periodic Reporting for period 1 - b-lactams C-H activation (Discovery of novel β-lactam analogs oriented to control multidrug-resistant bacteria enabled by Pd-catalyzed C–H activation of aliphatic amines)

Reporting period: 2015-05-01 to 2017-04-30

Methods that enable practical and selective functionalization of aliphatic systems are of significant importance to the continued advance of chemical synthesis. Over the last two decades, transition-metal catalysis has emerged as an effective means of C–H activation using polar functionalities such as heteroarenes, carboxylic acids, and amide derivatives to modulate the cyclometallation process. The natural evolution of the field is the use of native functional groups to direct such C-H activation process. Recently, palladium-catalyzed C–H functionalization of aliphatic amine derivatives has emerged as a potentially powerful tactic for the synthesis of complex variants of these important molecules.
While the functionalization of methyl C-H bonds have been explored, a major challenge remains the selective functionalization of methylene bonds. The activation of this class of bonds, on account of them being more sterically demanding than their primary counterparts, presents difficulties to both metal insertion and reductive elimination steps. Moreover, the functionalization of methtylene C–H bonds can generate stereogenic carbon centers, potentially causing stereoselectivity issues.
The main objective of this work is the development of a C-H activation approach to transform simple aliphatic amines into b-lactams.


During the last two years, we have developed first highly regio- and diasteroselective palladium-catalyzed carbonylation of methylene bonds in secondary aliphatic amines to furnish poly substituted trans-β-lactam scaffolds.

This new methodology enables to transform simple aliphatic amines into poly substituted b-lactams in one step. Given the broad tolerance of this reaction to useful functional groups, we believe that this C–H carbonylation process will be of significant interest to practitioners of synthesis and medicinal chemistry, specifically for accessing antibiotics.
The prevalence of aliphatic amines both in natural products and pharmaceutical agents renders their selective functionalization an invaluable tool to the synthetic community. Despite the importance of such chemical architectures, surprisingly few strategies have been developed to catalytically activate C–H bonds in aliphatic amines. Recently, our group reported the palladium catalyzed carbonylation of methyl bonds in simple aliphatic amines via a novel carbamoyl cyclopalladation pathway (Science, 2016, 354, 851), Figure 1a. In an effort to demonstrate the wide-ranging applications of this C–H activation mode, we began to explore whether the new carbonylation strategy would be capable of activating a methylene C–H bond in a range of aliphatic amines. In light of the novel carbamoyl cyclopalladation pathway, we sought to exploit this reactivity mode by selectively activating methylene bonds in the presence of methyl bonds in aliphatic amine systems (Figure 1b). Our studies started investigating the carbonylation of di(pentan-3-yl)amine 1 under standard catalytic carbonylation conditions (Figure 1c) affording the trans-β-lactam 2 in a promising 23% yield and high diastereoselectivity (d.r. = 12:1) (entry 1). Extensive screening of pyridine- and phosphine- based ligands, oxidants, additives and temperature revealed the optimal conditions (Figure 1c, entry 1-13). Subjection of 1 to 10 mol% Pd(OAc)2, 300 mol% AgOAc, 200 mol% 1,4-benzoquinone and 10 mol% Xantphos in toluene at 80 °C for 18 h afforded 2 in 83% yield.
We focused our efforts to explore the generality of this transformation (Table 1). We observed that α-substituted cycloalkyl amines 4 proved to be inert under our reaction conditions, exclusively affording the corresponding products by activation on the branched alkyl substituent. Also, we found β-quaternary amines furnished the corresponding products 5 in good yields, including a highly acid-sensitive oxetane ring 6. Interestingly, cyclopentyl derived amines were found to activate exclusively the ring methylene C–H bonds, affording the fused β-lactam 7 in a 66% yield. Less sterically demanding groups including methylene-cyclohexyl 8 as well as substituents displaying known palladium coordinating moieties such as thioethers 9 were also compatible with our reaction conditions. Electron poor arenes afforded the corresponding β–lactams 10 in decent efficiency. Our methodology could also be successfully applied to the functionalization of pharmaceutical derivatives, transforming a propranolol analogue into the desired β-lactam in a good yield and selectivity 11. We further tested our reaction conditions on challenging substrates containing linear alkyl substituents. Despite competing deleterious pathways, n-hexyl derived amine delivered 12 in a modest 40% yield. To our surprise nitrogen-containing heteroaromatics, known to coordinate palladium and direct C–H activation processes, proved compatible with our methodology delivering the desired β–lactams 13 and 14 in good yields without any competing side reactions. We then interrogated the selectivity of our reaction in substrates displaying multiple methylene bonds in different chemical environments (15-20). Despite the greater reactivity of benzylic C–H over unsubstituted alkyl C–H bonds, selectivity proved poor (1.5:1) 15. Surprisingly, C–H bonds adjacent to heteroatoms proved to be completely inert under our reaction conditions, allowing the regioselective activation of protected β-amino alcohols bearing esters 16 and heteroaromatics 17 in good efficiency. Pleasingly, the amino alcohols derived from phenylalanine gave the desired product 18 without any activation of the more reactive C(sp2)–H bonds. The high levels of selectivity were also translated into amino-pyrrolidine substrates, resulting in a single bicyclic product 19 in a 51% yield. To test the limits of selectivity in this C–H carbonylation process, we also prepared substrate (20), wherein four different methylene bonds are accessible to the Pd-carboxamide activation mode. Remarkably, we found that reaction took place at only one C–H bond (next to the ester) to form 21, highlighting a striking selectivity that seems to be inherent to this amine-directed carbonylation reaction. The disubstituted β-lactams could be readily transformed into useful building blocks: acidic methanolysis formed the β-amino ester derivative 24 in good yield; exhaustive reduction afforded the amino alcohol 23; and treatment with alane delivered the disubstituted azetidine 22 in good yield.
We have developed a robust reaction that transforms easily accessible aliphatic amines, into β–lactams cores in one step. The impact of this discovery is important since it provides a previously non-existent disconnection pathway in the synthesis these biologically important cores. We have shown that this new methodology will enable access to new scaffolds with potential biological application (chemical modification of drugs analogs such as propanolol)
The development of simple and robust transformations for the synthesis of β–lactams may play a crucial role in the pharmaceutical industry facilitating not only the synthesis of antibiotics but also the late stage functionalization of advance intermediates with promising biological effects. Both of these beneficial applications could certainly alleviate the overall cost of antibiotics, broadening the accessibility of antibacterial medical treatments.