Aziridines aziridine-containing molecules

Very reactive nitrogen mustards and aziridine-containing molecules are usually too toxic for general therapeutic use, but find use in neoplastic disease. Benzodepa (182) is such an agent. Treatment of ethyl carbamate with phosphorous pentachloride leads to cyanate 180 which readily adds benzyl alcohol to produce carbamate 181. Displacement of the active... 

It is extremely valuable to the organic chemist to know how aziridine-containing molecules can be structurally modified without loss of their aziridine ring. Select examples of aziridine synthesis from aziridine-containing molecules include stereo-controlled lithiation/electrophile... 

Pashkevich and Khomutov [111] reported the synthesis of aziridines containing polyfluoroalkyl substituents on the aziridine cycle. In the case where RF is CF3, the only reaction product is bis(aziridinyl ketone) 103 (Scheme 1.28). The results also provide information about the reaction mechanism. As well as in [107], it is assumed that the reaction proceeds via the formation of a-bromo-ketones and /5-aminoketones 101 and 102 where the next step is the intramolecular bromine substitution and heterocyclization into quinoxaline 104. But in the case where RF is CF3, the formation of the aziridine cycle is followed by the interaction of the second amino group of the diamine with another molecule of the intermediate 102, leading to compound 103. 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

Fused-ring aziridines have found broad application to the synthesis of complex natural products. The ability of these fused-ring aziridines to be converted to other nitrogen-containing molecules under mild conditions with wide functional group compatibility makes these heterocycles quite useful. 

All these studies set up the basis to apply this class of organocatalysts in MIRC-type processes for the synthesis of cyclopropane-containing molecules. Indeed, these compounds are, together with epoxides and aziridines, among the most useful cyclic scaffolds, present in several biological relevant products and pharmaceuticals. 

The two-bond disconnection (re/ro-cycloaddition) approach also often works very well if the target molecule contains three-, four-, or five-membered rings (see section 1.13 and 2.5). The following tricyclic aziridine can be transformed by one step into a monocyclic amine (W. Nagata, 1968). In synthesis one would have to convert the amine into a nitrene, which-would add spontcaneously to a C—C double bond in the vicinity. 

In molecules containing two cyclobutenes, addition of organic azides 26 yielded two adducts, e.g. reaction with 50 with benzyl azide 56 produced the cr-isomer 57a in which the (V-benzyl substituents were sy -aligned and the C2-isomer 57b in which they were anti-orientated (Scheme 7). The structure of syn-isomer 57a was confirmed by X-ray (Figure 2). The fact that both isomers yielded the same fns-aziridine 58 upon photolysis made separation of the individual triazoline isomers unnecessary. 

This section covers the synthesis of aziridines, oxiranes, /J-lactams and oxetanes. Aziridines are fairly important moieties in bioactive molecules and thus new routes for their synthesis are constantly being developed. /1-Lactams are probably the most important heterocyclic compounds that contain a single nitrogen atom, due to their importance in penicillin and cephalosporin chemistry. Their synthesis and chemistry has received much attention and much of this work has been reviewed544. The oxygen-containing heterocycles are much less commonly synthesized from double-bonded functional groups. 

Pyrrolizidine alkaloids ( )-trachelanthamidine (240) and ( )-supinidine (244) were synthesized, based on the Michael addition of an aziridine to an a,/J-unsaturated ester and subsequent ring opening of an aziridinium intermediate. Interest in these alkaloids stems from their biological activities. Treatment of ethyl 6-chloro-2-hexenoate (236) with excess aziridine at 0°C gave the pyrrolidine derivative 238 in one step, probably via the aziridinium salt 237 in 73% yield. The intramolecular cyclization of 238 with lithium diisopropylamide in tetrahydrofuran provided the thermodynamically more stable ester 239 as the sole product, (86%), which was then converted to ( )-trachelanthamidine (240) by reduction with lithium aluminum hydride. Since necine bases must contain a 1,2-didehydro system in their molecule to exhibit physiological activity, the following reactions were carried out to introduce a 1,2-didehydro system. Treatment of 238 with 2.4 equiv of lith-... 

In a larger molecule convergence will be slower. On the right side of Fig. 47 similar results are reported for the aziridine molecule. The expansion containing terms up to octopole is sufficiently accurate for distances more than 3 A from the center of the molecule. Another test is to analyze the errors introduced by using the multipolar expansion. 

Many types of reactive molecules are well known to medicinal chemists acyl halides, aldehydes, aliphatic esters, aliphatic ketones, alkyl halides, anhydrides, alpha-halocarbonyl compounds, aziridines, 1,2-dicarbonyl compounds, epoxides, halopyrimidines, heteroatom-heteroatom single bonds, imines, Michael acceptors and (l-heterosubstituted carbonyl compounds, perhalo ketones, phosphonate esters, thioesters, sulfonate esters, and sulfonyl halides, to name a few [14]. This is not to say that these functionalities are not useful - some even appear in approved drugs -but all of these can react covalently with proteins, and thus should be regarded with suspicion. However, molecules can react covalently with proteins even if they do not contain functionalities that raise alarm. Jonathan Baell has referred to these as pan assay interference compounds, or PAINS, and has published a list of moieties to watch out for, as well as strategies to detect them [15, 16]. 

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