Cyclic asymmetric 1,3-dipolar cycloaddition

Nitronate Facial Selectivity in Intermolecular [3+2] Cycloadditions of Nitronates The majority of asymmetric dipolar cycloadditions of nitronates have been investigated in the context of the tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes. With chiral, cyclic nitronates, the facial selectivity is primarily controlled by the steric environment that defines the diastereotopic faces of the nitronate. Nitronates obtained from [4 + 2] cycloadditions with vinyl ethers contain an acetal stereocenter that controls the approach of the dipolarophile. Nitronate 103 (Scheme 16.26) reacts with dimethyl maleate to produce predominantly nitroso acetal distal- QA through a distal approach of the dipolarophile [23]. The proximal approach provided the minor isomer with dr 7/l. Calculations suggest that the distal approach of the dipolarophile that leads directly to a chair-Uke conformation of the six-membered ring is slightly favored over the proximal approach [121]. 

The reactions of nitrones constitute the absolute majority of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions. Boron, aluminum, titanium, copper and palladium catalysts have been tested for the inverse electron-demand 1,3-dipolar cycloaddition reaction of nitrones with electron-rich alkenes. Fair enantioselectivities of up to 79% ee were obtained with oxazaborolidinone catalysts. However, the AlMe-3,3 -Ar-BINOL complexes proved to be superior for reactions of both acyclic and cyclic nitrones and more than >99% ee was obtained in some reactions. The Cu(OTf)2-BOX catalyst was efficient for reactions of the glyoxylate-derived nitrones with vinyl ethers and enantioselectivities of up to 93% ee were obtained. 

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

The carbo- and hetero-Diels-Alder reactions are excellent for the constmction of six-membered ring systems and are probably the most commonly applied cycloaddition. The 1,3-dipolar cycloaddition complements the Diels-Alder reaction in a number of ways. 1,3-Dipolar cycloadditions are more efficient for the introduction of heteroatoms and are the preferred method for the stereocontrolled constmction of five-membered heterocycles (1 ). The asymmetric reactions of 1,3-dipoles has been reviewed extensively by us in 1998 (5), and recently, Karlsson and Hogberg reviewed the progress in the area from 1997 and until now (6). Asymmetric metal-catalyzed 1,3-dipolar cycloadditions have also been separately reviewed by us (7-9). Other recent reviews on special topics in asymmetric 1,3-dipolar cycloadditions have appeared. These include reactions of nitrones (10), reactions of cyclic nitrones (11), the progress in 1996-1997 (12), 1,3-dipolar cycloadditions with chiral allyl alcohol derivatives (13) and others (14,15). 

Cyclic nitrones with substituents a to the nitrogen atom (38) undergo 1,3-dipolar cycloaddition with methyl propiolate to form isoxazolo[2,3-a]pyridines (39) and (40) with high regio- and stereo-specificity (Scheme 14).64 The chiral cyclic nitrones (41) undergo asymmetric 3 + 2-cycloaddition reaction with a, /i-unsaturated carbonyl compounds to form cycloadducts (42) with very high diastereomeric excess (>99%) (Scheme 15).65... 

Chiral crotonates derived from S-citroncllol, l-(—)-menthol, and S-solketol undergo 1,3-dipolar cycloaddition with cyclic and acyclic nitrones.66 Asymmetric 1,3-dipolar cycloaddition of optically active hifluoromethylated a, /l-unsaturated aiyl sulfones (43) with nitrones yield the corresponding isoxazolidmes (44) and (45) with high regio- and... 

The chemo-, regio-, and stereo-selective 1,3-dipolar cycloaddition of C-aryl-iV-phenylnitrones with 3,5-bis(arylidine)-l-methylpiperidin-4-ones produced mono- and bis-spiroisoxazolidines, with the former predominating.52 The 1,3-dipolar cycloaddition of five-membered cyclic nitrones with a, fl-unsaturated y-lactones provides an interesting example of a double asymmetric induction.53 Eu(fod)3 catalysed the ... 

The DFT study of the 3 + 2-cycloaddition between ketene and TV-silyl-, IV-germyl-, and TV-stannyl-imines shows that the TV-germylimine reaction is a two-step process the TV-stannylimine reaction is a competition between two- and three-step processes whereas the TV-silyl process follows a three-step process44 A new and convenient synthesis of functionalized furans and benzofurans based on 3 + 2-cycloaddition/oxidation has been reported. The cyclization of cyclic 1,3-bis-silyl enol ethers (48) with l-chloro-2,2-dimethoxyethane (49), via a dianion, produced 5,6-bicyclic 2-alkylidenetetrahydrofurans (50), which are readily oxidized with DDQ to 2,3-unsubstituted benzofurans (51) (Scheme 13)45 The Evans bis(oxazoline)-Cu(II) complex catalyses the asymmetric 1,3-dipolar cycloaddition of a -hydroxyenones with nitrones to produce isoxazolidines.46 The... 

Recent work has focused on developing catalytically controlled asymmetric 1,3-dipolar cycloadditions of cyclic nitrones such as 2,3,4,5-tetrahydropyridine IV-oxide 174. The Lewis acid iron complex 181 catalyzes the cycloaddition of 2,3,4,5-tetrahydropyridine jV-oxide 174 with methacrolein to give (3A,5A)-isoxazolidine 182 in good yield and high enantiomeric selectivity (Scheme 48) <2002JA4968>. The same catalyst 181 however gave (3R,4A,5R)-isoxazolidine 183 with much lower selectivity when crotonaldehyde was used. 

These results indicate that the sulfinyl group seems to be much more efficient in the control of the stereoselectivity of 1,3-dipolar cycloadditions (endo or exo adducts are exclusively obtained in de> 80%) than in Diels-Alder processes (mixtures of all four possible adducts were formed). Additionally, complete control of the regioselectivity of the reaction was observed. Despite these clearly excellent results, the following paper concerning asymmetric cycloaddition of cyclic nitrones and optically pure vinyl sulfoxides was reported nine years later [154]. (Meanwhile, only one paper [155], related to the synthesis of /1-nicotyri-nes, described the use of reaction of nitrones with racemic vinyl sulfoxides, but these substrates were merely used as a masked equivalent of acetylene dipolaro-phile). In 1991, Koizumi et al. described the reaction of one of the best dipolarophiles, the sulfinyl maleimide 109, with 3,4,5,6-tetrahydropyridine 1-oxide 194 [154]. It proceeded in CH2C12 at -78 °C to afford a 60 20 10 6 mixture of four products in ca. 90 % yield (Scheme 92). 

Table 10.9 Asymmetric 1,3-dipolar cycloaddition of cyclic enones and azomethine imines.

Reports on the advances of asymmetric 1,3-dipolar cycloadditions include the reaction of diazoalkanes to 7V-(2-alkenoyl)oxazolidin-2-ones catalyzed by Mg or Zn complexes of 73, showing cooperative chiral control by the achiral oxazolidinone auxiliary and the chiral ligand.An intramolecular cycloaddition of the same kind from substrates containing a chiral cyclic AiA -dimethylaminal unit adjacent to the dipolarophilic double bond (i.e., 74) proves very successful in the asymmetric sense, although the reaction of an analogous nitrone lacks stereoselectivity. 

Cooper, D.M., Grigg, R., Hargreaves, S. ef a/. (1995) X = Y-ZH compounds as potential 1,3-dipoles. Part 44. Asymmetric 1,3-dipolar cycloaddition reaction of imines and chiral cyclic dipolarophiles. Tetrahedron, 51, 7791-7808. 

Asymmetric 1,3-dipolar cycloadditions of cyclic stabilized ylides derived from chiral 1,2-amino alcohols 06SL2349. 

Koizumi and coworkers have recently reported an asymmetric 1,3-dipolar cycloaddition between (i )-(+)-p-tolyl vinyl sulfoxide and cyclic dipoles such as 1-methyl-3-oxidopyridinium salt (263) to give the cycloadducts (264a), (264b), and (265) in the ratios shown (Scheme 5.86) [197]. The major cycloadduct results from addition of the dipolar species from the face of the sulfoxide containing the lone pair, assuming that the dipolarophile reacts from an s-frans conformation. 

In 2011 the same research group described another efficient application of dicarbo Q lic acids 63 in the asymmetric inverse-electron-demand 1,3-dipolar cycloaddition (lED 1,3-DC) of C//-cyclic azomethine imines with t-butyl vinyl ether or vinylogous aza-enamines (synthesized from enals) (Scheme 24.23). This latter reaction, carried out without exclusion of moisture and air, gave cycloadducts regioisomeric to the products observed in the normal-electron-demand 1,3-dipolar cycloaddition (NED 1,3-DC) catalysed by Ti/binolate starting from the enals and for this reason the authors introduced the concept of lED umpolung 1,3-DC. 

A year later, based on the same principle by using primary amine-catalyzed iminium ion activation in combination with external Brpnsted acid additives, Chen et al. [129] were able to achieve the asymmetric 1,3-dipolar cycloaddition of cyclic enones and a variety of azomethine imines in excellent yields and selectivities (Scheme 11.48). In this case, to scavenge the generated H2O during the formation of the enamine nucleophile intermediate, and to overcome the expected hydrogenbonding interaction, a stoichiometric amount of molecular sieves (4 A) was added. Interestingly, when the pseudoenantiomer catalyst 61 was employed, an opposite enantiomer of the product was formed in good yields and selectivities. 

Asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of C,A-cyclic azomethine imines with c-rich dipolarophiles was accomplished with a high stereo-selectivity by using an axially chiral dicarboxylic catalyst (40)." The metal-free silicon Lewis-acid-catalysed 3-1-2-cycloadditions of A-acylhydrazones with cyclopentadiene provides a mild access to pyrazolidine derivatives in excellent... 

The asymmetric 1,3-dipolar cycloaddition of C,A(-cyclic azomethine imines with unsaturated nitriles yielded chiral cyanopyrazolidines in good to excellent yields and... 

The asymmetric 3 + 2-cycloaddition of cyclic azomethine ylides with Oppolzer s acryloyl camphor sultam has been used for the construction of X-azabicyclo[7M.2.1] alkenes in optically pure form. The non-stereospeciflc 1,3-dipolar cycloaddition of electron-poor azomethine ylides and electron-rich enamines proceeds by a two-step mechanism via zwitterionic intermediates. The 1,3-dipolar cycloaddition of 4,6-diazaphenanthrene 6-phenacylide with a variety of dienophiles readily produces the fused heterocycles tetrahydrobenzo[/]pyrrolo[l,2-/z][l,7]naphthyridines. Sequential... 

Diastereoselective 1,3-Dipolar Cycloadditions. Several examples of high diastereofacial selectivity with homochiral dipolarophiles have been reported. Cycloaddition of (1) with the cyclic dipolarophile (3) occurs with complete r-facial selectivity as a result of addition from the side opposite the bulky sUyloxymethyl group (eq 4). The key step in an asymmetric synthesis of (S)-(—)-cucurbitine involves cycloaddition of (1) with the a,p dehydrolactone (4) to give the pyrrolidine (5) as a single diastere-omer (eq 5). ... 

The use of 27f, with bis(2-naphthyl)methyl groups at the 3,3 -positions, as a catalyst enabled the employment of C,N-cyclic azomethine imines as a dipole for the asymmetric inverse-electron-demand 1,3-dipolar cycloaddition with vinyl ethers as exemplified in Scheme 7.52 [79],... 

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