Alkynes-nitrones cycloaddition

Recent advances and applications of strain-promoted alkyne-nitrone cycloaddition reactions in bio-orthogonal labeling (14COCB81) and of natural isoxazoline derivatives in the field of anticancer research (14EJM121) were reviewed. 

Synthesis of p-lactams through alkyne—nitrone cycloadditions 13THC (30)85. 

Strain-promoted alkyne-nitrone cycloaddition (SPANC) is another example of a 1,3-dipolar cycloaddition that has been applied for biomolecule labeling. The reactivity of nitrones with strained alkynes can be finely tuned by varying the substitution pattern [46-48]. Various cyclic nitrones were found to react with superior kinetics when compared to their acyclic counterparts and were successfully... 

Ning XH, Temming RP, Dommerholt J, Guo J, Ania DB, Debets MF, Wolfert MA, Boons GJ, van Delft FL (2010) Protein modification by strain-promoted alkyne-nitrone cycloaddition. Angew Chem Int Ed 49(17) 3065-3068. doi 10.1002/anie.201000408... 

Temming RP, Eggermont L, van Eldijk MB, van Hest JCM, van Delft FL (2013) N-terminal dual protein functionalization by strain-promoted alkyne-nitrone cycloaddition. Org Biomol Chem 11(17) 2772-2779. doi 10.1039/c3ob00043e... 

Strain-promoted alkyne-nitrone cycloaddition and its application to protein modification have been reviewed along with other bioorthogonal strategies (13CC11007). 

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

Nitrone cycloaddition reactions with alkynes have been widely used for the synthesis of imidazolidine nitroxides (736) and (737), containing chelating enam-ino ketone groups (821). Different heterocyclic systems were obtained, such as 3-(2-oxygenated alkyl)piperazin-2-ones (738) (822), also compounds containing the isoxazolo[3,2-i]indole ring system (739) (823) and a new class of ene-hydroxylamino ketones- (l )-2-( 1-hydroxy-4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones (740) (824) (Fig. 2.46). 

The use of alkynes has been investigated in the context of intramolecular nitronate cycloadditions (130). In this case, the starting material is consumed in 24 h at room temperature, however, the corresponding isoxazoline is not isolated (Table 2.41). Instead, the intermediate cycloadduct undergoes a fragmentation which, following the loss of the nitroso moiety, leads to an a,p-unsaturated aldehyde. 

TABLE 2.41. INTRAMOLECULAR SILYL NITRONATE CYCLOADDITIONS WITH ALKYNES... 

Dihydroisoxazoles with a substituent at nitrogen are most conveniently prepared by 1,3-dipolar cycloaddition of nitrones to alkenes or alkynes. Nitrones are usually prepared in situ from carbonyl compounds and /V-(alkyl)hydroxylamines (Figure 15.10). 

In constrast with intermolecular nitrone cycloadditions to alkynes and allenes, very little work has been done on the corresponding intramolecular cycloadditions. The bicyclic isoxazolidines (65a-b) were reported as products from reaction of an alkynone with methylhydroxylamine in ethanol.26b Presumably the initial strained bridgehead C—C double bond of the AMsoxazoline added ethanol under the reaction conditions. Cyclization of an allenyl ketone with methylhydroxylamine in ethanol solution also led to isoxazolidines (65a-b) as the major products and isoxazolidine (66) as a minor product.266 Thus, preferential cyclization to the internal C—-C double bond of the allene occurred followed by addition of ethanol to the exocyclic C—C double bond of the methyleneisoxazolidine intermediate. 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

Namitharan and Pitchnmani (2011) proposed a novel Cu-catalyzed one-pot sul-fonyl azide-alkyne/ketenimine-nitrone cycloaddition sequence for the synthesis of imidazolidin-4-ones, which might be utilized as antimalarial and antiproliferative drugs. The heterogeneous version employing Cu(I)-zeolites as recyclable catalysts is attractive for its improved efficiency and diastereoselectivity (Scheme 4.54). In this case, a three-component heterogeneous domino process was utilized and a variety of imidazolidin-4-ones were synthesized in moderate to excellent yields. The products could be easily isolated by simple filtration. 

Namitharan, K. and Pitchumani, K. 2011. Copper(l)-catalyzed three component reaction of sulfonyl azide, alkyne, and nitrone cycloaddition/rearrangement cascades A novel one-step synthesis of imidazolidin-4-ones. Org. Lett. 13(21) 5728-5731. 

Fig. 8 N-terminal protein labeling using alkyne-nitrone 1,3-dipolar cycloaddition...

Nitrone hydrate is converted into nitrone by boiling in benzene with azeotropic removal of water [48] (equation 50). This in situ formation of nitrone is carried out in the presence of various alkenes and alkynes, which undergo cycloaddition with the nitrone [48, 49] (equations 51 and 52). 

In the frequency of their use in 1,3-dipolar cycloadditions to nitrones, alkynes constitute the second group of dipolarophiles after alkenes. They are of particular interest due to the fact that isoxazolines, the products of initial cycloadditions,... 

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

The [3+2] cycloaddition of terminal alkynes has been investigated with several dipoles. These dipolarophiles are competent in the cycloaddition, however, the corresponding isoxazolines cannot be isolated. Instead, the cycloadduct undergoes spontaneous rearrangement to provide acylaziridine products (Table 2.52) (229). Disubstituted alkynes also undergo this process, however, in lower yield. This rearrangement occurs with all nitronates studied (Chart 2.3) (66,230,231). 

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