Stereospecificity 1,3-dipolar cycloaddition reactions

The stereochemistry of the 1,3-dipolar cycloaddition reaction is analogous to that of the Diels-Alder reaction and is a stereospecific syn addition. Diazomethane, for example, adds stereospecifically to the diesters 43 and 44 to yield the pyrazolines 45 and 46, respectively. 

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the -enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>. 

The application of intramolecular dipolar cycloaddition reactions to the synthesis of complex natural products has recently come to be recognized as a very powerful synthetic tool, one equally akin to the intramolecular Diels-Alder reaction in its potential scope of application.69 This is particularly the case with nitrile oxides and the 1NOC reaction has been extensively utilized in total synthesis.70 The intramolecular nitrile oxide cycloaddition (INOC) generally displays exceptional regio- and stereo-chemical control which undoubtedly accounts for the popularity of this reaction. Internal cycloadditions of nitrile oxides have been found to offer a powerful solution to many problems in complex natural product synthesis.48 For example, Confalone and coworkers have utilized the INOC reaction for the stereospecific synthesis of the key amino alcohol (60), which was converted in five subsequent steps to ( )-biotin (61 Scheme 14).71... 

An intramolecular [3 + 2] dipolar cycloaddition reaction has also been exploited in the design of a concise, stereospecific synthesis of ( )-a-lycorane (57) (119). Thus, cyclization of the azomethine ylide 145, which was produced in situ by the reaction of 144 with IV-benzylglycine, in refluxing toluene furnished the cw-hydroindole 146 as the exclusive product (Scheme 14). The transformation of 146 to racemic a-lycorane (57) was then achieved by N-debenzylation via catalytic, transfer hydrogenation and subsequent Pictet-Spengler cyclization. 

Apparent poor stereospecificity characterizes these 1,3-dipolar cycloaddition reactions. Formation of two diastereoisomers from fnmarate might be the result of the possible two types of endo orientation of this olefin toward the ylid, and epimerization at the 3-position, due to the high acidity of the corresponding hydrogen might be responsible for the isomerization of the expected all-ds adduct to the final product.458... 

As measured by the criteria of stereospecificity, regioselectivity, kinetic isotope effects, and solvent effects [117-120, 541-543], 1,3-dipolar cycloaddition reactions represent orbital symmetry-allowed [n + n s] cycloadditions, which usually follow concerted pathways Diels-Alder reactions and 1,3-dipolar cycloadditions resemble each other, as demonstrated by the small solvent effects on their bimolecular rate constants. In going from nonpolar to polar solvents, the rate constants of 1,3-dipolar cycloadditions change only by a factor of 2... 10 [120, 131-134]. 

N-Benzyl-N-methoxyraethyl-N-(triraethylsily1jmethylamine undergoes stereo-specific cycloaddition with dimethyl maleate and fumarate. The cycloaddition behavior of an unsymnetrically substituted a-methoxysilylamine has also been examined and found to occur with high overall regioselectivity. The stereospecificity and regioselectivity of the reaction is consistent with a concerted 1,3-dipolar cycloaddition reaction. 

A number of stereospecific 1,3-dipolar cycloaddition reactions of the azomethine imine (385) with olefins have been reported. The dipole (386), generated as shown, has been trapped as the cyclo-adduct (387) to dimethyl fumarate. " The betaine (389) is formed in the reaction of 1,2-diphenyl-... 

Dipolar cycloaddition reactions were investigated by Huisgen and his co-workers. 1, 3-Dipolar cycloadditions provide a versatile method for stereospecific synthesis of five membered heterocyclic compounds by the addition of 1 3-dipolar compoimds to ethylenic and acetylenic double bonds (dipolarfiles). 1, 3-dipolar systems are four n-electron species which undergo Kg+n g concerted cycloadditions across ic-bonds of olefins and acetylenes. 

The theoretical principles of cycloaddition reactions are well understood and there have been many computational studies (see Pericyclic Reactions The Diels-Alder Reaction). Often the hetero-cycloaddition reaction shows similar characteristics to the carbocyclic analog, but a number of special features have been noted. In heterocyclic chemistry the cycloaddition reactions are often dipolar computational studies show that a concerted mechanism is followed in the gas phase. However, a number of studies have noted that these dipolar cycloaddition reactions become stepwise when solvent effects are included (via the reaction field method), with a consequent loss of stereospecificity." Other characteristics of hetero-cycloaddition reactions which have been studied include the endo/exo selectivity" and the regiose-lectivity (for example, [2-1-2] vs. [2-1-4])." High levels of electron correlation are generally required in order to establish these selectivities. 

General. Diphenyl phosphorazidate is a readily available, nonexplosive, and relatively stable azide widely used as a reagent in peptide synthesis, " and as a versatile reagent in a wide array of organic transformations. DPPA has been successfully utilized in the synthesis of a-amino acids and o-aryl carboxylic acids direct preparation of thiol esters from carboxylic acids and thiols the stereospecific preparation of alkyl azides and the phosphorylation of alcohols and amines The application of DPPA in a modified Curtius reaction permits a simple one-step conversion of carboxylic acids to urethanes under mild reaction conditions. DPPA acts as a nitrene source, and can undergo 1,3-dipolar cycloaddition reactions. The Curtius degradation of carboxylic acids in the presence of f-butanol gives the Boc-protected amine directly (eq 1). 

Ozonation ofAlkenes. The most common ozone reaction involves the cleavage of olefinic carbon—carbon double bonds. Electrophilic attack by ozone on carbon—carbon double bonds is concerted and stereospecific (54). The modified three-step Criegee mechanism involves a 1,3-dipolar cycloaddition of ozone to an olefinic double bond via a transitory TT-complex (3) to form an initial unstable ozonide, a 1,2,3-trioxolane or molozonide (4), where R is hydrogen or alkyl. The molozonide rearranges via a 1,3-cycloreversion to a carbonyl fragment (5) and a peroxidic dipolar ion or zwitterion (6). 

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS ... 

Concerted cycloaddition reactions provide the most powerful way to stereospecific creations of new chiral centers in organic molecules. In a manner similar to the Diels-Alder reaction, a pair of diastereoisomers, the endo and exo isomers, can be formed (Eq. 8.45). The endo selectivity in the Diels-Alder arises from secondary 7I-orbital interactions, but this interaction is small in 1,3-dipolar cycloaddition. If alkenes, or 1,3-dipoles, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated. Such selectivity is defined as diastereomeric excess (de). 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

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