mation]
Highly Reactive Four-Membered Ring Nitrogen Heterocycles. Synthesis and Properties
Benito Alcaide,1* Pedro Almendros2* & Cristina Aragoncillo1*
Addresses
1 Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Email: ,
Fax: +34-91-39444103
2 Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
Email:
Fax: +34-91-5644853
Four-membered nitrogen hetereocycles such as b-lactams (i.e. 2-azetidinones) and azetidines are useful substrates in organic chemistry for the design and preparation of biologically active compounds by the adequate functionalization in the different positions of the ring. In addition, they are also versatile building blocks for the synthesis of other types of nitrogen-containing compounds with potential biological properties.
Keywords: Azetidines, heterocycles, b-lactams, rearrangements, stereoselectivity, strain
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Introduction
For many years, b-lactams (i.e. 2-azetidinones) and azetidines have catched the attention of organic chemists and medicinal researchers. The importance of the stereoselective synthesis of b-lactams is ever increasing in light of structure-activity relationship studies and the development of new derivatives of b-lactam antibiotics, inhibitors of b-lactamases and b-lactam derivatives with anticancer properties [1, 2]. In addition, it has been recognized the usefulness of b-lactams as potential building blocks for the preparation of all kind of nitrogen-containing target compounds [3]. On the other hand, the azetidine ring is present in natural products of interest. Besides, the strained nature of the azetidine skeleton has been employed as a synthetic tool for the preparation of higher nitrogen heterocycles with potential biological activity [4]. This review summarizes recent reports on different aspects related to the preparation and properties of these four-membered nitrogen heterocyclic rings and their biological activities. In particular, most of the examples collected in this review have been published in the past two years. However outstanding previous reports have been included as well. This review is divided in two sections, namely b-lactam and azetidine rings. First, for each section, we discuss the most representative and novel synthetic methodologies for constructing the four-membered nitrogenated rings. Next, the syntheses and properties of novel monocyclic, fused, spirocyclic, and bridged b-lactam and azetidine derivatives have been reviewed. Finally, we have selected a variety of examples concerning the usefulness of b-lactams and azetidines in synthesis, for the preparation of different types of interesting nitrogen-containing compounds.
b-Lactams
Synthesis of the b-lactam skeleton
There is a high number of synthesis of monocyclic b-lactams [5]. However, classical methods such as the Staudinger reaction (Scheme 1A) [6, 7], (which usually affords predominantly the cis-diastereomer, although altering the nature of the substrates and reaction conditions can often promote the formation of trans-isomer) [8, 9], and the Gilman-Speeter reaction (Scheme 1B) [10] (reaction of enolates with imines) are the most general synthetic methods employed so far. In addition, a typical approach involves the preparation of b-amino acids or esters followed by cyclization (Scheme 1C). For example, the research group of Melchiorre has described the enantioselective synthesis of amino esters via Mannich reaction and subsequent cyclization under acidic conditions [11]. The corresponding b-lactams have been obtained in excellent yields and enantioselectivities. On the other hand, the Kinugasa reaction [copper (I) catalyzed cycloaddition of a terminal alkyne and a nitrone] represents an elegant approach toward b-lactams because of its wide scope [12]. The reaction involves ring opening of methyleneaziridine 1 promoted by a Grignard reagent and a catalytic amount of CuI, followed by capture of the resultant metalloenamine with an electrophile (R3X). Subsequent addition of glacial acetic acid followed by in situ generated ketene afforded the corresponding b-lactams 2, via Staudinger [2+2] cycloaddition, in moderate yields.
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Scheme 1. Synthesis of the b-lactam ring via Staudinger [2+2] cycloaddition reaction (A), Gilman-Speeter reaction (B) and by cyclization of b-amino acids or esters (C).
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On the other hand, there are only a few examples for the catalytic enantioselective Staudinger reaction. Leckta has been the pioneer to report the reaction of ketenes with N-tosyl a-iminoesters in presence of quinine derivatives to afford b-lactams with high enantioselectivities [14]. Later on, Fu has reported the reaction of ketenes with N-tosyl and N-triflyl imines to afford cis- and trans-b-lactams, respectively, using planar-chiral derivatives of 4-(dimethylamino)pyridine as catalyst [15]. More recently, the research group of Ye has demonstrated the efficiency of N-heterocyclic carbenes to catalyze the Staudinger reaction of ketenes with imines (Scheme 2B) [16]. Under optimized conditions, the authors have reported that a wide variety of ketenes 3 and imines 4 smoothly react to afford the corresponding b-lactams 5 in good yields with high diastereoselectivities and excellent enantioselectivities.
Design, synthesis and properties of monocyclic, fused, spirocyclic, and bridged b-lactams
The b-lactam ring is the central motif of the main drugs used for the treatment of diseases caused by bacterial infections. The increased resistance of bacteria to traditionally used b-lactam antibiotics and the ever growing new applications of these products in enzyme inhibition, have triggered a renewed interest in the design and synthesis of new systems having the b-lactam ring in their structure.
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Scheme 2. Synthesis of b-lactams via Staudinger [2+2] cycloaddition reaction.
Boc tert-butoxycarbonyl, ee enantiomeric excess, TBS tert-butyldimethylsilyl.
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The research group of Marchand-Brynaert has prepared a library of 30 b-lactams from an acetoxy-azetidinone, to test the inhibition of human fatty acid amide hydrolase (hFAAH) [17]. The 2-azetidinone ring has been functionalized with lateral chains imitating the structure of the inhibitors, in order to make hydrophobic contacts in the active site of the target enzyme. To design this library, the authors have studied the chain length (nPr, nBu) and the nature of the end group (aromatic or aliphatic) for both substituted positions [N(1) and C(5)-O]. Acetoxy-azetidinone 6 has been transformed into N-acylated b-lactams 7 in two steps (Scheme 3A). Esterification of compounds 7 with acyl chlorides and pyridine produced the corresponding azetidinones 8 in good yields. Compounds 8 have been identified as inhibitors of hFAAH versus human monoacylglycerol lipase (hMGL), with IC50 values in the nanomolar range (5-14 nM).
In recent years, there is a growing interest in the design of complex structures based on the combination of two potential biological molecules. For example, in 2008, Palomo and colleagues have reported the synthesis of saccharide/b-lactam hybrid peptide-mimetic as potential lectin antagonist [18]. The design has been carried out according to a “shape-modulating linker” using the Cu(I) catalyzed variant of the Huisgen 1,3-dipolar cycloaddition (“click chemistry” methodology). Thus, cycloaddition reaction of propargyl-b-lactams 9 with O-protected 2-azidosugars derived from D-mannose and L-fucose has led to a clean and completely anomer-specific reaction to form glycoconjugated b-lactams 10 in excellent yields (Scheme 3B). The demonstration that these molecules could act as glycomimetics of modulable shape has been achieved by a combined NMR/docking approach employing a model fucose-bending lectin, Ulex Europaeus Lectin I (UEL-I), as receptor. The authors have observed a clear interaction between the L-b-fucose-substituted mimetic and UEL-I. A recent related work has been reported by Iadonisi et al [19]. This research group has prepared a hybrid structure of the glycopeptide antibiotic mannopeptimycin disaccharide by anchoring the b-lactam ring in presence of a Lewis acid.
Usually, the search for new b-lactam drugs has been focused on the design of strained bicyclic 1,4-fused
structures in order to increase the acylating power of the amide moiety in the b-lactam ring. A high number of novel structures, including small, medium and large rings fused to the b-lactam skeleton have been prepared applying different cyclization processes. Thus, the interest on the design and preparation of fused, spirocyclic and bridged b-lactams has growed up [20].
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Scheme 3. Design and synthesis of monocyclic b-lactams as potential selective inhibitors.
Py pyridine, TBS tert-butyldimethylsilyl, Ns 2-nitrobenzenesulfonyl.
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5-Oxacephams is a family of interesting b-lactam antibiotics and b-lactamase inhibitors [21]. In 2009, Chmielewski et al have reported the enantioselective synthesis of 3,4-benzo-5-oxacephams via intramolecular nucleophilic substitution at C(4) of the starting 4-formyloxy-azetidinones in presence of a chiral Lewis acid [22]. Monocyclic b-lactams 11 were treated with a stoichiometric amount of SnCl4 and (S)-3,3'-bis-a-naphtyl-BINOL 12 as ligand to afford the corresponding 5-oxacephams 13 with excellent enantiomeric excess in moderate yields (Scheme 4A). The authors have explained the low yields in terms of a kinetic resolution of the initially formed racemic oxacephams. This mechanism has been supported by the partial asymmetric destruction of racemic product 13 in presence of the chiral catalyst.
4-Hydroxypipecolic acids are natural nonproteinogenic amino acids. This skeleton is present in many biologically active natural and synthetic products such as depsipeptide antibiotics [23], and HIV protease inhibitors such as palinavir [24]. In 2008, two syntheses of novel 4-hydroxypipecolic acid analogues with a bicyclic b-lactam structure have been published [25]. One of the synthesis is shown in Scheme 4B and involves hydrogenation reaction of azido b-lactam 14 followed by the addition of benzyl chloroformate to give the 4-hydroxypipecolic acid analogue 15 in 49% yield.
Recently, Marchand-Brynaert et al have investigated a new family of bicyclic 2-azetidinones, in which the b-lactam skeleton is embedded in a 1,3-bridging large ring [26]. Thus, this research group has designed and prepared four families of 1,3-bridged 2-azetidinones, as potential inhibitors of penicillin-binding proteins, via ring-closing metathesis [27]. Ring closing metathesis of alkenyl 2-azetidinones 16 afforded 1,3-bridged azetidinones 17 in high yields (Scheme 5). Catalytic hydrogenation of compounds 17 furnished b-lactams 18 quantitatively. Biochemical evaluation of compounds 17 and 18 against the b-lactamase TEM-1 from E-coli has shown no activity at a concentration of 100 mM. Interestingly, the authors found that 1,3-bridged b-lactams 17 and 18 were active to R39 inhibitor (an enzyme usually used for a preliminary screening of penicillin-like compounds), whereas the monocyclic precursors 16 were inactive. In addition, evaluation of b-lactams 16-18 against a set of high-molecular-weight D,D-peptidases responsible for bacterial resistance to b-lactam antibiotics showed week to modest activity.
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Scheme 4. Synthesis of fused b-lactams.
Cbz benzyloxycarbonyl, PMP p-methoxyphenyl, BINOL 1,1'-bi-2,2'-naphthol.
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Scheme 5. Synthesis of bridged b-lactams.
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Chartellines are a family of marine alkaloids, isolated from Chartella papyracea, with an exquisitely complicated architecture formed by three biologically important heterocycles: indolenine, imidazole and b-lactam [28]. The asymmetric synthesis of the spiro-b-lactam core of chartellines has been published by the research group of Iwabuchi [29]. The synthetic strategy starting from indole 19 using 5 mol% of rhodium catalyst 20 to give spirocycle 21, involves the formation of the nitrogen-substituted spirocenter, via aziridine intermediate 22 (Scheme 6). The following five steps include ozonolysis of the exo-methylene moiety, N-Boc protection and reduction of the carbamate followed by oxidation to give b-amino alcohol 23. Finally, lactamization of compound 23 in the presence of tris(2-oxo-3-benzoxazolinyl)phosphine oxide yielded enantioenriched spiro-b-lactam 24.
In recent years, much effort has been expended in the preparation of bis-b-lactams, as potential starting materials for the synthesis of functionalized macrocycles, with potential applications in supramolecular chemistry [30]. For example, the synthesis of bis-b-lactams via a tandem Cu-promoted alkyne-homocoupling followed by double [2+2] allenyne cycloaddition has been reported [31].
Taking into account that the b-lactam ring system in combination with 1,2,3-triazole moiety is present in a number of drugs such as the anti b-lactamase tazobactam and the cephalosporin cefatrizine, Hazra and co-workers have reported the synthesis, as well as the antimicrobial and cytotoxic activities of bis-b-lactams linked through 1,2,3-triazole ring [32]. Synthesis of b-lactamic hybrids has been achieved using the “click chemistry” methodology between b-lactamic azides 25 and alkynes 26 in a mixture of tBuOH-H2O (7:3) with CuSO4·5H2O and sodium ascorbate at 70ºC (Scheme 7). Dimeric compounds 27 have been obtained in excellent yields. The dimers prepared were tested in vitro for antifungal and antibacterial activity using a variety of fungal strains against Escherichia coli and Staphylococcus aureus. Most of the dimers have shown moderate to good antifungal and antibacterial activity. However, only one of the compounds 27 showed comparable activity to that of tetracycline and ampicillin against S. aureus with a MIC value of 16mg mL-1. In addition, the authors have reported that compounds 27 did not show any significant cytotoxicity to the tested cell lines.
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Scheme 6. Synthesis of the spiro-b-lactam core of chartellines.
Boc tert-butoxycarbonyl.
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Scheme 7. Design, synthesis and biological evaluation of dimers linked with bis-b-lactam and 1,2,3-triazole.
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Synthesis and properties of nitrogen-containing compounds from b-lactams
Besides the key role of b-lactams as potential antibiotics, additional impetus on b-lactam chemistry has been provided by the introduction of the b-lactam synthon method, a term coined by Ojima [33], according to which 2-azetidinones can be employed as useful building blocks in organic synthesis [3]. Taking into account the ring strain of the b-lactam moiety along with the adequate functionalization in the different positions of the ring, a variety of nitrogen-containing target compounds can be obtained. In addition, it is important to consider that most of the contributions described are unexpected transformations.
The pyrrolidine skeleton is present in many natural products and pharmacologically active compounds [34]. In particular, polyhydroxylated pyrrolidines, dihydroxylated pyrrolidin-2-ones and their synthetic analogues have attracted a great deal of attention due to their biological activities, such as glycosidase inhibitors [35]. It has been recently published the unexpected reaction of b-lactams, in presence of a catalytic amount of iodine, to give hydroxylated pyrrolidin-2-ones [36]. Reaction of C(3) alkoxy-substituted formyl-b-lactams 28 in presence of tert-butyldimethylsilyl cyanide using iodine as catalyst afforded the expansion products, pyrrolidinone derivatives 29, in reasonable yields and good to excellent diastereoselectivities, instead the expected addition products (cyanohydrins) to the carbonyl group of the aldehyde (Scheme 8A).