Diels-Alder reaction recognizing products

The reaction is carried out simply by heating a diene or another conjugated system of n bonds with a reactive unsaturated compound (dienophile). Usually the reaction is not sensible to catalysts and light does not affect the course. Depending on the specific components, either carboxylic or heterocyclic products can be obtained. The stereospecificity of the reaction was firmly established even before the importance of orbital symmetry was recognized. In terms of orbital symmetry classification, the Diels-Alder reaction is a k4s + n2s cycloaddition, an allowed process. 

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... 

The retrosynthesis of this compound by Batey and co-workers [96] recognized that the unprecedented hexahydropyrrolo[3,2-c]quinoline core could be synthesized using a three-component Pavarov hetero-Diels-Alder reaction [97]. For this synthetic strategy to be successful, however, reaction conditions that favor the exo approach of the dienophile over the endo approach had to be found. For this purpose, a variety of protic acids were tested, and it was found that the reaction was best carried out in the presence of camphorsulfonic acid (CSA). Indeed, a mixture of 4-aminobenzoate 200 and N-Cbz 2-pyrroline 201 were stirred at room temperature in the presence of catalytic CSA to afford exo cyclo-adduct 203 as the major product (Scheme 12.28). The N-Cbz 2-pyrroline served as both an aldehyde equivalent and a dienophile in this context. The Diels-Alder adduct 203 already bore all the requisite functionalities for the successful completion of the synthesis, which was achieved in six additional steps. 

The participation of diradical species in charge transfer reactions has been demonstrated in the most widely recognized example of donor-acceptor interaction—i.e., the Diels-Alder reaction. The two-step nature of this reaction has recently been proposed in the isolation of both four-and six-membered ring products in the thermal and photochemical reaction of butadiene and a-acetoxyacrylonitrile (14, 56). 

The presence of the triphenylphosphonium substituent makes 351 (Scheme 2.122) an active dienophile. Resulting cycloadducts such as 352 are immediately recognized as precursors for the formation of ylides. Products with an exocyclic double bond such as 353 are easily synthesized via a tandem sequence of Diels-Alder and Wittig reactions. The formation of adduct 353 could have been achieved via the Diels-Alder reaction with the allene CH2 = C = CHR, but this direct route is generally unapplicable owing to the low activity of allenes as dienophiles. 

A wide range of hetero 2-aza-1,3-butadienes have been shown to participate as 4rr components of Diels-Alder reactions (Figure 4). Perhaps the most widely recognized class of hetero 2-aza-1,3-butadienes is the A -acylimines (l-oxa-3-aza-l,3-butadiene) ° and comprehensive reviews of their 4tt participation in LUMOdiene-controlled Diels-Alder reactions are available. The recent disclosure of the 4ir participation of A -acylimines in intramolecular [4 + 2] cycloaddition reactions (equation 11), and the use of optically active A -acylimines in productive LUMOdiene-controlled [4 + 2] cycloaddition reactions, illustrate applications of the systems that have not been explored fully (equation 12). ... 

Oxazoles represent the most widely recognized heteroaromatic azadiene capable of [4 + 2] cycloaddition reactions. The course of the oxazole Diels-Alder reaction and the facility with which it proceeds are dependent upon the dienophile structure (alkene, alkyne), the oxazole and dienophile substitution, and the reaction conditions. Alkene dienophiles provide pyridine products derived from fragmentation of the [4 + 2] cycloadducts which subsequently aromatize through a variety of reaction pathways to provide the substituted pyridines (Scheme 14). In comparison, alkyne dienophiles provide substituted fiirans that arise from the retro Diels-Alder reaction with loss of R CN from the initial [4 + 2] cycloadduct (Scheme 15,206 Representative applications of the [4 + 2] cycloaddition reactions of oxazoles are summarized in Table 14. Selected examples of additional five-membered heteroaromatic azadienes participatiitg in [4 + 2] cycloaddition reactions have been detailed and include the Diels-Alder reactions of thiazoles, - 1,3,4-oxadiazoles, isoxazoles, pyrroles and imidazoles. ... 

On PhI(OAc)2-promoted oxidation in CH2CI2 containing alkenol (5 equiv.) at room temperature, 2-methoxyphenols such as 421 (R = Me and COOMe) were converted into the corresponding tricyclic compounds (444 and 445) in 77 and 75% yields, respectively (Scheme 86) via an intramolecular Diels-Alder reaction of the initially formed cyclohexa-2,4-dienones (446 and 447). These tricyclic compounds are recognized as promising synthetic intermediates for synthesis of natural products and related compounds . ... 

Electrophilic sulfenes, R2CMSO2, are recognized for their ability to react with nucleophiles and for their 2ir participation in [2 + 2] and [4 + 2] cycloadditions (Chapter 5). Less well recognized is the demonstrated 4ir participation of vinyl sulfenes in Diels-Alder reactions with a select set of dienophiles. Thermolysis of thiete 1,1-dioxides including the parent thiete 1,1-dioxide (22) in the presence of norbornenes provided the Diels-Alder products derived from 4w participation of the vinyl sulfenes [Eq. (18)].40... 

Until recently, the reaction of a,/3-unsaturated esters with electron-rich olefins has been reported to afford cyclobutane [2 + 2] cycloaddition products. Amice and Conia first proposed the intermediacy of [4 + 2] cycloadducts in the reaction of ketene acetals with methyl acrylate,108 and the first documented example of the 4v participation of an a,/3-unsatu-rated ester in a Diels-Alder reaction appears to be the report of Snider and co-workers of the reversible, intramolecular cycloaddition of 1-allylic-2,2-dimethyl ethylenetricarboxylates.142 Subsequent efforts have recognized that substitution of the a,/3-unsaturated ester with a C-3 electron withdrawing substituent permits the 4w participation of such oxabutadiene systems in inverse electron demand Diels-Alder reactions with electron-rich olefins. In the instances studied, the rate of the [4 + 2] cycloaddition showed little dependence on solvent polarity [ aeetomtnie/ cycio-hexane — 3, Eq. (15) j acctomtnic toiuene 10, Eq. (20)], and reactions generally... 

Acylnitroso compounds are best recognized for their ability to participate as dependable 2ir components of Diels-Alder reactions with dienes, and these observations have found substantial application in the total synthesis of natural products (Chapter 3).81 However, Mackay and coworkers have detailed the isolation of 5,6-dihydro-1,4,2-dioxazine 9a (10%) from the reaction of acylnitroso 7a with cyclopentadiene [Eq. (39)]. ... 

When the cyclobutadienecarboxylate 21 [35] stabilized by the presence of bulky substituents, is allowed to react with the phosphaalkynes 9a-d, the 2-phospha-Dewar-benzenes are obtained in quantitative yields [36] (Scheme 6-5). For steric reasons the [4 + 2]-cycloaddition takes place at Cl and C4 and is highly selective with regard to the dienophile orientation. In the cases of the phosphaalkynes 9a-c, products 22a-c dominate over the isomers 24a-c by a ratio of at least 93 7. Within the detection limits of P-NMR spectroscopy, the Diels-Alder reaction 21 + 9d furnishes 22 d exclusively. The structure of 22 d was confirmed by X-ray crystallography [36]. The phosphaalkene moieties of the phospha-Dewar-benzenes 22a-d, which are utilized in the subsequent reactions, can be recognized, among others, by their low-field P-NMR signals (5 = 312-315). 

The number of reaction types that we have covered to this point is extensive enough to allow the construction of relatively complicated products from simple, readily available starting materials. Thus, recognizing that the bicyclo[2.2.2]octene derivative shown is accessible by a Diels-Alder reaction leads us back to cyclohexanol as the source of six of its carbons. 

Dimerization.—Unsaturated acids, whether monoenoic or polyenoic, furnish dimers which are in demand because of the valuable surface-active properties of their various derivatives. Methods of dimerization have therefore been extensively examined, but understanding of the reaction and the structural identification of the products have lagged behind. Dimerization is effected in several ways but clay catalysts are the most widely employed, and it is now recognized that such catalysts operate in several ways. They may promote modification of monoenoic and dienoic acids to more reactive monomers in addition to assisting both the dimerization process and the subsequent changes in the dimer molecules. In particular, hydrogen transfer seems to be important monoenoic acids are thereby converted to more reactive dienoic acids and the dimer (probably a cyclohexene derivative resulting from Diels-Alder reaction) is converted to a substituted aromatic compound. ... 

Right from the discovery of the Diels-Alder reaction in 1928, its importance in the synthesis of natural products was recognized. From early syntheses (such as cortisone) to more contemporary examples highlighted previously, the Diels-Alder reaction continues to play a prominent role in the synthesis of complex natural products. 

It is well recognized that the Diels-Alder reaction is a powerful method for constructing functionalized, six-membered carbocyclic compounds, especially in the synthesis of structurally complex natural products. Organocatalytic versions of enantioselective Diels-Alder reactions have also been explored for the synthesis of natural products. 

The interest of the nitroso Diels-Alder reaction has been well recognized for the synthesis of natural products that contain a jyn-4-aminocyclohexanol skeleton. Yan and coworkers reported on the enantioselective synthesis of the... 

Unfortunately, this reaction has not yet reached its fid potential for the stereoselective total synthesis of natural products. It is easy to recognize that piperazic acid derivatives 201 could develop from an azo Diels-Alder reaction. These nonproteinogenic cyclic a-hydrazino acids are widely found in depsipeptide natural products like the antimycobacteria lydiamycins 202 isolated from the fermentation broth of Streptomyces lycidus or in cdazapril 203 an angiotensin-converting enzyme inhibitor used as an antihypertensive drug by Hoffman-Laroche (Scheme 41.43). ... 

Isobenzofurans have long been recognized as outstanding dienes for the Diels-Alder and other cycloaddition reactions leading to oxabicyclo products. A 1988 review appeared in which the progress in the chemistry of isobenzofurans and the chemical transformations of oxabicyclo adducts has been intensively discussed <88X2093 >. 

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