Diels-Alder cycloaddition regioselectivity

Another example, in which the piperidine cycle is generated de novo, exploits a hetero Diels-Alder cycloaddition of 1 -/r-tolylsulfinyl-1,3-penta-diene 91 with benzylnitrosoformate, that generates an oxazine 92 with complete regioselectivity and 7i-facial diastereoselectivity.69 Osmilation of the double bond inserts stereoselectively two hydroxyl groups on the oxazine skeleton, protection and catalytic hydrogenation finally afforded the enantiomerically pure imino sugars 94 (Fig. 38). 

Details of various routes to allylphosphine oxides (43) have been reported, and the subsequent synthesis of 1,3-dienes has been illustrated by many examples.37 Also described are stereochemical aspects of these diene syntheses and of subsequent Diels-Alder cycloaddition reactions.37 High regioselectivity is observed in migrations of the diphenylphosphinoyl group from unsymmetrical sites, as in (44), in that both products have a double bond exocydic to the cyclohexane ring.38... 

Regioselective syntheses of 1,3,5-unsymmetrically substituted benzenes (309) are catalyzed by Pd(dba)2/PPh3 mixed alkyne/diyne reactants give mixtures containing homocoupled and mixed products (24 21 from HC CPh + HC=CC= CC Hn). The probable mechanism involves oxidative addition to the Pd(0) center, insertion of the second diyne into the Pd—H bond, reductive coupling and subsequent jr-complexation of this product to Pd(0), followed by Diels-Alder cycloaddition of the third diyne and elimination of product. 

An unusual Diels-Alder cycloaddition involving the Cp=Cy bond has been described. The reaction took place by treatment of the electron-deficient allenylidene moiety in complex [RuCp(=C=C=CPh2)(CO)(P -Pr3)][BF4] (46) with a 20-fold excess of isoprene at room temperature affording the cycloadduct 90 (Scheme 33) [287]. This Diels-Alder cycloaddition in which the allenylidene moiety acts as a dienophile was completely regioselective, only the Cp=Cy bond of the allenylidene skeleton being implicated. Furthermore, it was also regioselective with regard to the orientation of the diene with the exclusive attack of C(l) and C(4) carbons at the Cp and Cy positions, respectively. Allenylidene 46 also underwent Diels-Alder reactions with cyclopentadiene and cyclohexadiene to afford the... 

Fig. 6.2. HOMO-LUMO interactions rationalize regioselectivity of Diels-Alder cycloaddition reactions.

Molecular electrostatic potentials have been used to explain the regioselectivity exhibited in the Diels-Alder cycloaddition reactions between 1-trimethylsilyloxy-butadiene and the quinones 5-formyl-8-methyl-1,4-naphthoquinone, 5-methoxy-7-methyl-1,4-phenanthrenequinone, and 5,6,7-trimethyl-1,4-phenanthrenequinone.128 The intramolecular Diels-Alder reaction of masked o-benzoquinones (123) with a variety of dienes provides adducts (124) which rearrange to functionalized ris-decal ins (125) with complete stereocontrol of up to five stereocentres. This methodology ... 

Ethylene [17,18] or monosubstituted alkenes [18-20] have been used to carry out the CM step (Scheme 8). In this latter case, the presence of either oxygen or nitrogen at the propargylic position seems to have an influence on the regioselectivity of the incorporation of the CM partner. The extension of this reaction to cyclic enones produces trienes, able to perform intramolecular Diels-Alder cycloaddition reactions giving fused tricyclic products [21]. 

Regioselective Diels-Alder cycloadditions of nitropyrroles have been utilized to prepare hydroxyindoles <07TL1435>. For example, treatment of 2-nitropyrrole 65 with Danishefsky s diene 66 led to the production of 5-hydroxyindole 67. 

In yet another investigation, these workers determined that 585-CN is susceptible to electrophilic attack at the 5-position, nucleophilic attack at the 1- (or 3-) position, dienophile attack at the 4,5-position, and Diels-Alder cycloaddition at its electron-deficient ring.437) The differences in regioselectivity are impressive. 

Bromo-2-pyrone is not only a valuable precursor for the synthesis of various 3-substituted 2-pyrones,7 but it is also a reactive unsymmetrical diene.8 3-Bromo-2-pyrone undergoes Diels-Alder cycloadditions with a regioselectivity and stereoselectivity that is superior to that of 2-pyrone. Furthermore, 3-bromo-2-pyrone is a chameleon (i.e., ambiphilic) dienophile, undergoing cycloaddition to both electron deficient and electron rich dienophiles. The cycloadducts of bromopyrone with dienophiles are isolable and are useful in the synthesis of diastereomerically pure cyclohexene carboxylates (Scheme 2).8... 

With 1,1-disubstituted trifluoromethylated alkenes, such as a-(trifluoromethyl)styrene, cycloaddition w ith nitrone 1 is regioselective, and a 50 50 mixture of the ais/ /ranj-isomers is obtained, as observed in Diels-Alder cycloaddition reactions (see Section 2.1.1.6.2.1.1.).5 When the reaction is performed solvent-free under microwave irradiation, instead of under thermal conditions (boiling toluene), the yield is improved from 65% to 98% and the reaction time decreases from 48 hours to 4 minutes, however, stereoselectivity is not improved.79... 

Cycloadditions with these heterodienophiles are usually regioselective and are in accord with FMO theory. The reactions are syn selective with the diene component. Other stereochemical features of the process are outlined in some of the examples described below, as well as in previous reviews. -" It should also be mentioned that only aldehydes and some ketones act as dienophiles. Except for rare exceptions, other types of carbonyl compounds apparently do not participate in Diels-Alder cycloadditions. 

Beak has reported an aromatic ring anneladtm using ortho lithiatitm to regioselectively introduce an aldehyde, which is then converted to a carbene. Subsequent Diels-Alder cycloaddition of the resultant isobenzofurans result in adducts that may be oxidized to n q>hthalenes or reduced to tetralins. A typical example is shown in Scheme 9. 

The first total synthesis of the marine furanosesquiterpenoid tubipofuran was accomplished in the laboratory of K. Kanematsu. The c/s-fused furanodecalin system was constructed by the regioselective Diels-Alder cycloaddition reaction of benzofuran quinone and Danishefsky s diene in refluxing toluene. The reaction gave an 11 1 mixture of the desired ortho-endo adduct versus the undesired para-endo product in 98% isolated yield. The major isomer then was subjected to sequential radical deoxygenation reactions before it was finally converted to the natural product. 

In summary, we predict the regioselectivity of a Diels-Alder cycloaddition by the following sequence ... 

A -Acyl-l,2-dihydropyridines undergo regioselective Diels-Alder cycloadditions with nitrosobenzene [Eq. (5)]. ... 

Table 2-II lists a number of representative imino Diels-Alder cycloadditions using acyclic IV-acylimines and Ai-acyliminium dienophiles. In general, cycloadditions using C.iV-diacylimino systems (entries 1-10) and unsymmetrical dienes show good regioselectivity. The adducts from these reactions have the regiochemistry one would predict based on Scheme 2-1...

In addition to the [4 + 2] cycloadditions of oxazoles (Section 1) and substituted 1,2,4,5-tetrazines (Section 14), the Diels-Alder cycloadditions of substituted 1,2,4-triazines constitute one of the most thoroughly investigated heteroaromatic azadiene systems capable of 4tt diene participation.3,89 In contrast to the oxazole or sym-tetrazine series, two potential and observed modes of cycloaddition are open to 1,2,4-triazines cycloaddition across C-3/C-6 or C-5/N-2 of the 1,2,4-triazine nucleus, and the former is subject to 1,2,4-triazine substituent control of the observed regioselectivity.90 The complementary addition of electron-withdrawing substituents to the 1,2,4-triazine nucleus generally increases its rate of participation in inverse electron demand Diels-Alder reactions, influences the mode of [4 + 2] cycloaddition (C-3/C-6 versus C-5/N-2 cycloaddition), and controls the observed regioselectivity. In addition, the reactivity of the electron-rich dienophile as well as the reaction conditions, polar versus nonpolar solvent, have a pronounced effect on the observed course of the [4 -I- 2] cycloadditions.89... 

The Diels-Alder cycloaddition reaction of dihydropyran with acrolein was performed in the presence of various H-form zeolites such as H-Faujasites, H-p, H-Mordenites which differ both in their shape selective as well as their acidic properties. The activity of the different catalysts was determined and the reaction products were identified. High 3delds in cycloadduct were obtained over dealuminated HY (Si/Al=15) and Hp (Si/Al=25) compared to HM (Si/Al=10). These results were accounted for in terms of acidity, shape selectivity and microporosity vs mesoporosity properties. The activity and the regioselectivity were then discussed in terms of frontier orbital interactions on the basis of MNDO calculations for thermal and catalyzed reactions by complexing the diene and the dienophile with Bronsted and Lewis acidic sites. From these calculations, Bronsted acidic sites appeared to be more efficient than Lewis acidic sites to achieve Diels-Alder reactions. 

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