Endo-selective reaction

The Lewis acid-catalyzed reaction of nitrone 21 with ethyl vinyl ether 22 (Scheme 8.8) was also investigated for BH3 and AlMe3 coordinated to 21 [32]. The presence of BH3 decreases the activation energy for the formation of 23 by 3.1 and 4.5 kcal mol to 9.6 kcal mol for the exoselective reaction and 11.6 kcal-mol for the endo-selective reaction, respectively, while the activation energy for the formation of 24 increases by >1.4 kcal mol , compared to those for the uncatalyzed reaction. The transition-state structure for the BH3-exo-selective 1,3-dipolar cycloaddition reaction of nitrone 21 with ethyl vinyl ether 22 is shown in Fig. 8.19. 

Carbene complexes which have an all-carbon tether between the diene and the dienophile react via intramolecular Diels-Alder reaction to give the corresponding bicyclic compound. The stereoselectivities of these reactions are comparable to those observed for the Lewis acid-catalysed reactions of the corresponding methyl esters and much higher than those of the thermal reactions of the methyl esters which are completely unselective. Moreover, the ris-sub-stituted complexes undergo endo-selective reactions where the corresponding reaction of the ester fails [109] (Scheme 61). 

Aversa and colleagues168 studied the facial selectivities in the reactions of (5s)- and (Z s)-3-alkylsulfinyl-l-methoxy-l,3-butadienes with several dienophiles. Table 11 summarizes the results of the completely endo selective reaction of 258 with /V-phenylmaleimide (165) and the effects of different catalysts on the diastereofacial selectivity of this reaction (equation 71)168e. In the case of the uncatalyzed reaction, the dienophile attacked the... 

Pericas and coworkers173 studied the endo selective reactions of 1-alkoxy-l,3-butadienes and 1-alkoxy-l,3-octadienes with maleic anhydride. They found that the trans-2-phenyl-cyclohexan-l-ol and 3-exo-(neopentyloxy)isobornan-l-ol based chiral dienes induced the highest facial selectivities. The relative transition state energies for the formation of the different diastereomers were calculated using semi-empirical methods (AMI). 

As illustrated in Scheme 10, the CAB catalyst also effectively catalyzes the intramolecular Diels-Alder reaction of trienal 8 to afford bicyclic product 9 in high diastereo- and enantioselectivity [58]. In a single step, this endo-selective reaction achieves the formation of a tetrahydroindane ring system containing a stereogenic quaternary center. 

The TiX2-TADD0Late-catalyzed 1,3-dipolar q cloaddition reactions were extended to include an acrylate derivative [66]. In the absence of a catalyst, the reaction between nitrones 1 and acryloyl oxazolidinone 19b proceeded to give a mixture all eight regio-and stereoisomers (Scheme 6.23). However, application of in this case only 10 mol% of Ti(OTs)2-TADDOLate 23d as catalyst for the reaction of various nitrones 1 with alkene 19b, led to complete regioselectivity and high endo selectivity in the reaction and the endo products 21 were obtained with 48-70% ee (Scheme 6.23) [66]. 

In 1997 the application of two different chiral ytterbium catalysts, 55 and 56 for the 1,3-dipolar cycloaddition reaction was reported almost simultaneously by two independent research groups [82, 83], In both works it was observed that the achiral Yb(OTf)3 and Sc(OTf)3 salts catalyze the 1,3-dipolar cycloaddition between nitrones 1 and alkenoyloxazolidinones 19 with endo selectivity. In the first study 20 mol% of the Yb(OTf)2-pyridine-bisoxazoline complex 55 was applied as the catalyst for reactions of a number of derivatives of 1 and 19. The reactions led to endo-selective 1,3-dipolar cycloadditions giving products with enantioselectivities of up to 73% ee (Scheme 6.38) [82]. In the other report Kobayashi et al. described a... 

It has been more difficult to obtain the exo isomer in the above described reaction. Application of the TiCl2-TADDOLate complex induced fair exo selectivity and up to 60% ee. This was improved by the application of succinimide as an auxiliary for the alkene. This approach has been the only entry to a highly exo selective reaction and up to 72% ee of the exo isomer was obtained. In the Pd(BF4)2-BI-NAP-catalyzed reaction which gave mixtures of the endo and exo isomers, high ee of up to 93% was in a single case obtained for the minor exo isomer. In one case it was also observed that a Zn(OTf)2-BOX complex induced some exo selectivity and up to 82% ee of the exo isomer. 

Among the J ,J -DBFOX/Ph-transition(II) metal complex catalysts examined in nitrone cydoadditions, the anhydrous J ,J -DBFOX/Ph complex catalyst prepared from Ni(C104)2 or Fe(C104)2 provided equally excellent results. For example, in the presence of 10 mol% of the anhydrous nickel(II) complex catalyst R,R-DBFOX/Ph-Ni(C104)2, which was prepared in-situ from J ,J -DBFOX/Ph ligand, NiBr2, and 2 equimolar amounts of AgC104 in dichloromethane, the reaction of 3-crotonoyl-2-oxazolidinone with N-benzylidenemethylamine N-oxide at room temperature produced the 3,4-trans-isoxazolidine (63% yield) in near perfect endo selectivity (endo/exo=99 l) and enantioselectivity in favor for the 3S,4J ,5S enantiomer (>99% ee for the endo isomer. Scheme 7.21). The copper(II) perchlorate complex showed no catalytic activity, however, whereas the ytterbium(III) triflate complex led to the formation of racemic cycloadducts. 

The parent five-membered nitronate having no substituent at the 3-position was too unstable to be isolated. However, 3-substituted derivatives were highly stabilized. Especially, the 3-ethyl derivatives having a terminal electron-withdrawing substituent are readily available by the dehydrochlorination of 3-chloro-l-nitropropane in the presence of electron-deficient alkenes. It was our delight that the reaction of 3-al-kyl-substituted five-membered nitronates was also successfully catalyzed by R,R-DBFOX/Ph-Ni(SbFg)2 complex to at room temperature. This reaction was highly endo-selective (cisjtrans= 91 9) and enantioselective for the endo cycloadduct (92% ee). 

An important contribution for the endo selectivity in the carho-Diels-Alder reaction is the second-order orbital interaction [1], However, no bonds are formed in the product for this interaction. For the BF3-catalyzed reaction of acrolein with butadiene the overlap population between Cl and C6 is only 0.018 in the NC-transi-tion state [6], which is substantially smaller than the interaction between C3 and O (0.031). It is also notable that the C3-0 bond distance, 2.588 A, is significant shorter than the C1-C6 bond length (2.96 A), of which the latter is the one formed experimentally. The NC-transition-state structure can also lead to formation of vinyldihydropyran, i.e. a hetero-Diels-Alder reaction has proceeded. The potential energy surface at the NC-transition-state structure is extremely flat and structure NCA (Fig. 8.6) lies on the surface-separating reactants from product [6]. 

For the uncatalyzed reactions the calculations showed that the ortho approaches were favored over the meta, and the endo selectivity was the energetic most favorable reaction paths for most of the electron-donating substituents studied [29]. The endo-ortho reaction path is under FMO control and the substituent effect on the regios-electivity was explained for by a dominant interaction between LUMOdiene id HOMOdienophUe- The ortho reaction path was investigated with BH3 as the Lewis acid and it was calculated that the presence of Lewis acid decreases the activation... 

Recently, enhanced endo selectivity has been reported in the Diels-Alder reaction of fE -l-acetoxybuta-l,3-dienes with methyl fi-nitroacrylate The selectivity is compared with that of the reaction using l-methoxybuta-l,3-dienes and 1-trimethylsilyloxybuta-1,3-di-enes The degree of electron richness of a diene is an important consideration in endo eKO selectivity issues In particular, electron-rich dienes favor the formation of fixc-nitrocycload-ducts fEq 8 9 ... 

Optically active bicyclo[2.2,2]octanes can be obtained via diastercoselective MIMIRC reaction of lithium dienolates and a,/ -unsaturated esters of various chiral alcohols. Good yields (70-90%), high endo selectivities (> 95%) and diastereomeric ratios that depend on the auxiliary alcohol are found in these additions. The highest diastereomeric ratio reached was 18 82 using a camphor derived sulfonamide. The diastereomeric ratio could be improved (up to 9 91) by titanium(IV) chloride catalyzed addition of the corresponding silylenolates with the chiral a,/J-unsaturated esters358. 

A high endo selectivity is observed in the reaction of (phenylsulfonyl)allene (112) with furan (157) (equation 113)108. The endo adduct 158 can be readily transformed into highly substituted cyclohexenol 160 upon treatment with n-butyllithium after hydrogenation of the ring double bond (equation 114)108. 

Enantiomers, preferential crystallization of 59 Endo selectivity 798 Ene reactions 808, 809 Enones, synthesis of 732 Enthalpies of formation 102, 103 Enynes, synthesis of 956 Enzymatic kinetic resolution 829 Epimerization 399 Episulphides, oxidation of 237 Episulphones 650, 775 Episulphoxides, photolysis of 742 a,/J-Epoxysulphones reactions of 811, 812 rearrangement of 685 synthesis of 612 / ,y-Epoxysulphones 781 y,<5-Epoxysulphones 627, 628 Epoxysulphoxides reactions of 613 rearrangement of 744 synthesis of 327, 612 Erythronolides 831... 

An asymmetric version of this reaction was achieved by the use of complexes derived from chiral imidazolidinones. For example, the reaction of Danishefsky s diene with these chiral complexes occurs with both high exo endo selectivity and high facial selectivity at the dienophile [103] (Scheme 56). 

Exclusively endo-selectivity Lewis-acid catalyzed /jetero-Diels-Alder reactions of (E)-1-phenylsulfonyl-3-alken-2-ones with vinylethers [102]... 

The photo-induced exo selectivity was observed in other classic Diels-Alder reactions. Data relating to some exo adducts obtained by reacting cyclopentadiene or cyclohexadiene with 2-methyl-1,4-benzoquinone, 5-hydroxynaphtho-quinone, 4-cyclopentene-l,3-dione and maleic anhydride are given in Scheme 4.13. The presence and amount of EtsN plays a decisive role in reversing the endo selectivity. The possibility that the prevalence of exo adduct is due to isomerization of endo adduct under photolytic conditions was rejected by control experiments, at least for less reactive dienophiles. 

An endo-selective ionic Diels-Alder reaction of a,/f-enone and a,/f-enal acetals catalyzed by electrogenerated acid [99]... 

Lithium trifluoromethanesulfonimide in acetone or diethyl ether as a safe alternative to lithium perchlorate in diethyl ether for effecting Diels-Alder reactions. Unexpected influence of the counterion on exo/endo selectivity [47]... 

Scheme 26 Endo-selectivity of the Diels-Alder reactions and orbital phase environments...

Regioselectivities [7] and endo selectivity [8, 9] increase upon Lewis acid catalysis of Diels-Alder reactions (Scheme 9). Houk and Strozier [10] found that protonation on the carbonyl oxygen of acrolein amplifies the LUMO at the terminal and... 

Secondary orbital interactions (SOI) (Fig. 2) [5] between the non-reacting centers have been proposed to determine selectivities. For example, cyclopentadiene undergoes a cycloaddition reaction with acrolein 1 at 25 °C to give a norbomene derivative (Fig. 2a) [6]. The endo adduct (74.4%) was preferred over the exo adduct (25.6%). This endo selectivity has been interpreted in terms of the in-phase relation between the HOMO of the diene at the 2-position and the LUMO at the carbonyl carbon in the case of the endo approach (Fig. 2c). An unfavorable SOI (Fig. 2d) has also been reported for the cycloaddition of cyclopentadiene and acetylenic aldehyde 2 and its derivatives (Fig. 2b) [7-9]. The exo-TS has been proposed to be favored over the endo- IS. 

Mataka and coworkers further studied the exo/endo selectivity of outside attack products in the reactions of 96 and 97 with A-(5-X-phenyl)maleimides [56]. They found that the endo/exo selectivity is markedly dependent on the electronic nature of the substituent X (Scheme 47). The electro-withdrawing substituents such as NOj and Cl enhance enrfo-selectivity. The relative order of the enr/o-selectivity is NOj > Cl > H > OCH3. 

Both inter- and intra- molecular Diels-Alder reactions of 2-benzopyran-3-ones occur with high endo-selectivity and have been used to synthesise (-)-podophyllotoxin (14) and 4a-substituted cis-BC fused hexahydrophenenthrenes (15), respectively <96JCS(P1)151, 96JCS(P1)705>. 

The reaction of 1-thiabuta-1,3-dienes with di-(-)-menthyl fumarate exhibits high endo-selectivity when carried out thermally or when catalysed by Lewis acids. In both cases, the preferred product is the 3,4-cis-dihydrothiopyran (23) which is a source of optically pure diols <96JCS(P1)1897>. 

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