Cycloadditions inverse-demand

Stereoselective inverse-demand hetero (4 + 2) cycloadditions. A Chiral Template for C-Aryl Glycoside Synthesis. Chiral allenamides2 4 had been used in highly stereoselective inverse-demand hetero (4 + 2) cycloaddition reactions with heterodienes.5 These reactions lead to stereoselective synthesis of highly functionalized pyranyl heterocycles. Further elaboration of these cycloadducts provides a unique entry to C-aryl-glycosides and pyranyl structures that are common in other natural products (Scheme 1). 

The Pettus group has also developed three methods (F-H, Fig. 4.26) enabling low-temperature, inverse demand cycloadditions of o-QM intermediates. Jones and Selenski began by investigating the reactions of styrenes with o-OBoc benzalcohols... 

Akiyama applied Im in the inverse-demand aza-Diels-Alder reaction of various acyclic and cyclic vinyl ethers with N-aryl imines derived from o-hydroxyaniline to provide ophcally active tetrahydroquinoline derivatives (Scheme 5.16) [29]. Since aldimines derived from p-methoxyaniline gave no cycloaddition product, a nine-membered cyclic TS (akin to that proposed for the author s Mannich reachon) was invoked to rationalize the high levels of enantio-control. 

Acylchromones can undergo efficient inverse demand [4+2] cycloadditions with electron rich olefins. For a leading reference see Wallace, T. W., Wardell, I., Li, K.-D., Leeming, P., Redhouse, A. D., Chanlland, S. R., J. Chem. Soc., Perkin Trans. 11995, 2293, and references cited within. 

Inverse demand Diels-Alder cycloadditions of electron-rich nitriles with electron-deficient heteroaromatic dienes are also known. Typical examples of inter- and intra-moleculai instances of this process are shown in equations (29) and (30), respectively. 

Taylor and Raw recently designed a tethered imine-enamine cascade sequence that converts 1,2,4-triazenes into substituted pyridines. In the presence of molecular sieves, A-methylethylenediamine (147) underwent condensation with excess cyclic ketone 148 (n — 1-4) to give imine-enamine 150 (04CC508). The enamine portion of the molecule then participated in an inverse-demand Diels-Alder cycloaddition reaction with 149 to provide intermediate 151. Cycloreversion of 151 with loss of N2 then gave 152 in which the tertiary amino group underwent addition to the adjacent imine functionality to afford zwiterionic 153. Finally, an intramolecular Cope elimination produced 154 in 74-100% yield. Several other triazines were also shown to participate in this novel cascade (Scheme 27). 

Inverse demand cycloaddition of isoquinolinium salt 1 to chiral enol ethers, acetals and ortho esters 2 gives diastereomeric tetralins 3 and 4 with the diastereoselectivity depending on the nature of the dienophile and on the chiral auxiliary1. The primary tricyclic adduct solvolyzes to the tetralinaldehyde acetal in acidified alcohol. 

Inverse demand Diels-Alder reactions of tetrazines 1 to psoralenes 267 were reported to furnish tetracyclic pyridazine dicarboxylates 268, which were used as the key intermediates in the synthesis of nitrogenated isosteres of potent DNA inhibitors <2003T8171>. In some cases, cycloaddition was followed by opening of the furan ring to give pyridazinyl-substituted coumarins 271 (Scheme 66) <2000JHC907, 2003SL2225>. 

This reaction was first reported by Kondrat eva in 1957. It is a general method for synthesizing pyridine derivatives involving an inverse demand Diels-Alder Cycloaddition between an azadiene (especially the oxazoles) and a dienophile followed by an extmsion of the resulting bridge of the bicyclic intermediate. Thus this reaction is known as the Kondrat eva pyridine synthesis, Kondrat eva reaction, Kondrat eva cycloaddition,or Kondrat eva approach. " ... 

Formal inverse-demand [4 + 2] cycloaddition reaction of the in situ-generated cationic aryl 2-oxadiene oxocarbenium ions with electron-rich alkenes provides polysubstituted chromans in high yields. The diastereose-lectivity is dependent on the substitution pattern of the alkene generally... 

As shown in Scheme 11.35, the first [4+2] inverse-demand cycloaddition of electron-deficient heterodienes 166 to vinyl ether 158 was completely enDiels-Alder adduct and acrylate 156 showed a complete facial selectivity. 

In Section 5.3.1, an example of the typical reactivity of a-oxo-ketenes as 1-oxa-dienes in inverse demand oxa-Diels-Alder reactions was presented. It was recently discovered that in the presence of 1-aza-dienes, a-oxo-ketenes can also react as dienophiles in microwave-assisted aza-Diels-Alder cycloadditions, and this reactivity was exploited for the diastereoselective synthesis of a series of a-spiro-8-lactams (Scheme 5.4). Paralleling the three-component approach presented in Section 5.3.1, the microwave irradiation at 140 °C for 15 minutes of a 1 1 1 mixture of the 5,5-dimethyl-2-diazocyclohexan-l,3-dione 1, benzyl-amine, and cinnamaldehyde furnished the a-spiro-8-lactam... 

Pyridazine carboxylates and dicarboxylates undergo cycloaddition reactions with unsaturated compounds with inverse electron demand to afford substituted pyridines and benzenes respectively (Scheme 45). 

Most reactions discussed can be classified into two types of [n s+iAs cycloadditions, the normal and inverse electron-demand cycloaddition reactions, based on the relative energies of the frontier molecular orbitals of the diene and the dieno-phile (Scheme 4.2) [4]. 

The normal electron-demand reaction is a HOMOdiene-LUMOdienophUeelectron-rich dienes and electron-deficient dienophiles (Scheme 4.2, left dotted line). The inverse electron-demand cycloaddition reaction is primarily controlled by a LUMOdiene HOMOdienophiie inter-... 

INVERSE-ELECTRON DEMAND LUMO(jjend dienephile controliGd cycloaddition reactions... 

A simple approach for the formation of 2-substituted 3,4-dihydro-2H-pyrans, which are useful precursors for natural products such as optically active carbohydrates, is the catalytic enantioselective cycloaddition reaction of a,/ -unsaturated carbonyl compounds with electron-rich alkenes. This is an inverse electron-demand cycloaddition reaction which is controlled by a dominant interaction between the LUMO of the 1-oxa-1,3-butadiene and the HOMO of the alkene (Scheme 4.2, right). This is usually a concerted non-synchronous reaction with retention of the configuration of the die-nophile and results in normally high regioselectivity, which in the presence of Lewis acids is improved and, furthermore, also increases the reaction rate. 

The inverse electron-demand catalytic enantioselective cycloaddition reaction has not been investigated to any great extent. Tietze et al. published the first example of this class of reaction in 1992 - an intramolecular cycloaddition of heterodiene 42 catalyzed by a diacetone glucose derived-titanium(IV) Lewis acid 44 to give the cis product 43 in good yield and up to 88% ee (Scheme 4.31) [46]. 

Our development of the catalytic enantioselective inverse electron-demand cycloaddition reaction [49], which was followed by related papers by Evans et al. [38, 48], focused in the initial phase on the reaction of mainly / , y-unsaturated a-keto esters 53 with ethyl vinyl ether 46a and 2,3-dihydrofuran 50a (Scheme 4.34). 

The absolute configuration of products obtained in the highly stereoselective cycloaddition reactions with inverse electron-demand catalyzed by the t-Bu-BOX-Cu(II) complex can also be accounted for by a square-planar geometry at the cop-per(II) center. A square-planar intermediate is supported by the X-ray structure of the hydrolyzed enone bound to the chiral BOX-copper(II) catalyst, shown as 29b in Scheme 4.24. 

The inverse electron-demand 1,3-dlpolar cycloaddition reaction... 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

As for boron catalysts, the aluminum catalysts have exclusively been applied for the inverse electron-demand 1,3-dipolar cycloaddition between alkenes and nitrones. The first contribution to this field was published by j0rgensen et al. in... 

A quite different type of titanium catalyst has been used in an inverse electron-demand 1,3-dipolar cycloaddition. Bosnich et al. applied the chiral titanocene-(OTf)2 complex 32 for the 1,3-dipolar cycloaddition between the cyclic nitrone 14a and the ketene acetal 2c (Scheme 6.25). The reaction only proceeded in the presence of the catalyst and a good cis/trans ratio of 8 92 was obtained using catalyst 32, however, only 14% ee was observed for the major isomer [70]. 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

Furukawa et al. also applied the above described palladium catalyst to the inverse electron-demand 1,3-dipolar cycloaddition of nitrones with vinyl ethers. However, all products obtained in this manner were racemic [81]. 

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. 

Honk et al. concluded that this FMO model imply increased asynchronicity in the bond-making processes, and if first-order effects (electrostatic interactions) were also considered, a two-step mechanisms, with cationic intermediates become possible in some cases. It was stated that the model proposed here shows that the phenomena generally observed on catalysis can be explained by the concerted mechanism, and allows predictions of the effect of Lewis acid on the rates, regioselectivity, and stereoselectivity of all concerted cycloadditions, including those of ketenes, 1,3-dipoles, and Diels-Alder reactions with inverse electron-demand [2],... 

In an investigation by Yamabe et al. [9] of the fine tuning of the [4-1-2] and [2-1-4] cycloaddition reaction of acrolein with butadiene catalyzed by BF3 and AICI3 using a larger basis set and more sophisticated calculations, the different reaction paths were also studied. The activation energy for the uncatalyzed reaction were calculated to be 17.52 and 16.80 kcal mol for the exo and endo transition states, respectively, and is close to the experimental values for s-trans-acrolein. For the BF3-catalyzed reaction the transition-state energies were calculated to be 10.87 and 6.09 kcal mol , for the exo- and endo-reaction paths, respectively [9]. The calculated transition-state structures for this reaction are very asynchronous and similar to those obtained by Houk et al. The endo-reaction path for the BF3-catalyzed reaction indicates that an inverse electron-demand C3-0 bond formation (2.635 A... 

The final class of reactions to be considered will be the [4 + 2]-cycloaddition reaction of nitroalkenes with alkenes which in principle can be considered as an inverse electron-demand hetero-Diels-Alder reaction. Domingo et al. have studied the influence of reactant polarity on the reaction course of this type of reactions using DFT calculation in order to understand the regio- and stereoselectivity for the reaction, and the role of Lewis acid catalysis [29]. The reaction of e.g. ni-troethene 15 with an electron-rich alkene 16 can take place in four different ways and the four different transition-state structures are depicted in Fig. 8.16. 

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