Diels enantioselective inverse-electron

E. Marko, G. R. Evans, P. Seres, I. Chelle, Z. Janousek, Catalytic, enantioselective, inverse electron-demand Diels-Alder reactions of 2-pyrone derivatives, Pure Appl. Chem. 1996, 68, 113. 

J0rgensen and Juhl reported the first organocatalytic enantioselective inverse-electron-demand hetero-Diels-Alder reaction of aldehydes (e.g., 71) and enones (e.g., 72) with excellent diastereo- and enantioselectivity. Scheme 3.26 [41], The reaction utilizes a chiral enamine intermediate as an alkene in catalytic asymmetric cycloaddition reactions. 

Scheme 3.26 Enantioselective inverse-electron-demand Hetero-Diels-Alder reaction of aldehyde and enone...

A highly enantioselective inverse-electron-demand aza-Diels-Alder reaction of A-sulfonyl-l-aza-1,3-butadienes 88 and aldehydes 71 was reported by Chen and his co-workers. Scheme 3.31 [46]. Few chiral piperidine derivatives 89 were prepared via this methodology. The addition of water in the reaction media led to a dramatic acceleration of the reaction. Presumably, water is helpful for the hydrolysis of the catalyst-incorporated intermediate to release the catalyst and thus enable the catalytic turnover. Noteworthy, replacement of acetic acid to stronger acid, e.g. p-tolue-nesulfonic acid, resulted in no reaction. 

In addition to metal-based catalysts, organocatalysts are also selective promoters of asymmetric Diels-Alder reactions. Several groups reported the use of cinchona alkaloid catalysts in standard Diels-Alder reactions. Deng combined 2-pyrones with a,P unsaturated ketones, while Bernard and Ricci focused on the reactions of vinylindoles with quinones and maleimides. Lectka reported enantioselective inverse electron demand hetero Diels-Alder reactions of ketene enolates and o-benzoquininone diimides catalyzed by a combination of benzoylquinidine and zinc triflate. For example, subjecting diimide 51 to the standard reaction conditions yields cycloadduct 52 as a single stereoisomer, which can be easily converted to... 

Marko and coworkers applied the similar chiral Yb/BINOL/amine catalyst to enantioselective inverse-electron demand Diels-Alder reactions as shown in Scheme 13.22 [55]. When the reaction of 3-carbomethoxy-2-pyrone with phenyl vinyl sulfide was carried out in the presence of THF additive (5-10 mol equiv to Yb), the bicyclic lactone was obtained in 92% yield and in more than 95% ee. The use of the THF additive was essential to achieve high enantioselectivity. In the absence of the THF additive, the enantioselectivity decreased significantly. Vinyl ethers were also applicable as a dienophile, giving products in excellent selectivities. 

Employing a bifunctional enamine/metal Lewis acid catalyst enabled Wang and coworkers to perform a highly chemo-and enantioselective inverse-electron-demand hetero-Diels-Alder reaction of cyclic ketones with 8,y-unsaturated a-ketoesters (eq 12).21... 

In 2009, Feng and coworkers developed new guanidine catalysts with an amino amide skeleton [139]. Among the various catalysts tested, guanidine 49 was found to be the most active for the enantioselective Michael reaction of a (i-ketoester with nitroolefins (Scheme 10.46). The conjugate addition products were obtained in high yields and excellent diastereo- and enantioselectivities. The same researchers used bis-guanidine catalysts for the enantioselective inverse-electron-demand hetero-Diels-Alder reaction of chalcones with azlactones (Scheme 10.47) [140] and enantioselective Mannich-type reaction of a-isothiocyanato imide and sulfonyl imines (Scheme 10.48) [141]. 

Scheme 10.47 Enantioselective inverse-electron-demand hetero-Diels-Alder reaction of azlactones.

In 2003, the first organocatalytic enantioselective inverse-electron-demand hetero-Diels-Alder reaction of p,Y-unsaturated-a-ketones 97 with aldehydes 98 promoted by a secondary amine catalyst (99) was accomplished by the j0rgensen group (41). After oxidation by pyridinium chlorochromate (PCC), various trans-lactones 100 were afforded with good yields and up to 94% ee (Scheme 38.27). The reaction is proposed to occur via an enamine intermediate generated from chiral secondary amine 99 and aldehydes 98 (transition state O). Notably, sUica gel is essential for regeneration of the chiral amine catalyst. 

An enantioselective inverse-electron-demand hetero-Diels-Alder reaction of o-quinones 104 and aldehydes 98 was disclosed by the Dixon group with the use of secondary amine catalyst 105 [44]. This reaction went smoothly through in situ generated enamines with o-quinone reagents to afford the corresponding products 106 (with up to 81% ee), which can be further converted into optically active 2,3-dihydro-benzo[l,4]dioxin compounds (Scheme 38.28). 

In 2006, Bode and coworkers reported the first enantioselective inverse-electron-demand hetero-Diels-Alder reaction of enals 130 with a,(i-unsaturated imines 131 under the catalysis of carbene precatalyst 123 in combination with Hiinig s base [59]. A broad range of substrates were well tolerated to afford synthetically important dihydropyridinone products 132 in good yields with remarkable enantioselec-tivities (Scheme 38.38). The need to introduce electron-withdrawing groups for enals only lies within the increased electrophilicity of these substrates, which enhances the rate of their reaction with the nucleophilic catalysts. The observed... 

Inverse-Electron-Demand [4+2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas group s ingenious design of Diels-Alder reactions using enamine-activated dienes, Jprgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse-electron-demand hetero-Diels-Alder reaction (Scheme 1.24) [26]. 

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. 

Inverse electron-demand Diels-Alder reaction of (E)-2-oxo-l-phenylsulfo-nyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the Ri group of the dienophile, and the best result was obtained when Ri was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2-symmetric chiral Cu(II) complexes 83 (Scheme 3.16). 

Various substituted unsaturated acylphosphonates participate in highly dias-tereoselective and enantioselective cycloadditions with vinyl ethers, Eqs. 177 and 178. It is intriguing to note that catalysts [(.V,.Y)-f-Bu-box]Cu (OTf)2 (269c) and [(.V,.S )-Ph-box]Cu (OTf>2 (269d) possessing the same sense of chirality afford opposite antipodes of the cycloadduct in comparable selectivities. Cyclopentadiene was found to react with acylphosphonates to give a mixture of the normal Diels-Alder adduct and the inverse electron demand hetero-Diels-Alder adduct (35 65), Eq. 179. This result may be contrasted with crotonylimide, which furnishes the normal demand Diels-Alder adduct exclusively. 

Recently, the first examples of catalytic enantioselective preparations of chiral a-substituted allylic boronates have appeared. Cyclic dihydropyranylboronate 76 (Fig. 6) is prepared in very high enantiomeric purity by an inverse electron-demand hetero-Diels-Alder reaction between 3-boronoacrolein pinacolate (87) and ethyl vinyl ether catalyzed by chiral Cr(lll) complex 88 (Eq. 64). The resulting boronate 76 adds stereoselectively to aldehydes to give 2-hydroxyalkyl dihydropyran products 90 in a one-pot process.The diastereoselectiv-ity of the addition is explained by invoking transition structure 89. Key to this process is the fact that the possible self-allylboration between 76 and 87 does not take place at room temperature. Several applications of this three-component reaction to the synthesis of complex natural products have been described (see section on Applications to the Synthesis of Natural Products ). 

Chromium complex 53 was also shown to efficiently catalyze the inverse electron-demand hetero Diels-Alder reaction of a,(3-unsaturated aldehydes with alkyl vinyl ethers (Scheme 17.19).26 Although the uncatalyzed process required elevated temperatures and pressures to give dihydropyrans in good yields but poor endo. exo selectivities, the reaction proceeded at room temperature in the presence of 5 mol% of ent-53 and 4A molecular sieves in dichloromethane of tert-butyl methyl ether with excellent diastereoselectivity (endo. exo >96 4) and promising enantioselectivities (72-78% ee). Optimal results were achieved using a solvent-free system and excess vinyl ether. 

Akiyama T, Morita H, Itoh J, Fuchibe K (2005 a) Chiral Brpnsted acid catalyzed enantioselective hydrophosphonylation of imines asymmetric synthesis of alpha-amino phosphonates. Org Lett 7 2583-2585 Akiyama T, Morita H, Fuchibe K (2006b) Chiral Brpnsted acid-catalyzed inverse electron-demand aza Diels-Alder reaction. J Am Chem Soc 128 13070-13071... 

Inverse electron demand hetero-Diels-Alder reactions of acyl phosphonates or a-keto ester heterodienes and enol ethers are also catalyzed by (5, iS )-t-Bu-box complexes. High levels of enantioselectivity are obtained with y-alkyl-, -aryl-, -alkoxy-... 

Thorhauge, J, Johannsen, M, Jprgensen, K A, Highly enantioselective catalytic hetero-Diels-Alder reaction with inverse electron demand, Angew. Chem. Int. Ed., 37, 2404-2406, 1998. 

A conceptually different [4-1-2] cycloaddition catalyzed by a chiral lanthanide complex has been disclosed. The inverse electron demand Diels Alder reaction of 3-methoxycarbonyl-2-pyrone (67) and enol ethers or sulfides [135] was catalyzed by a chiral ytterbium(III) triflate-binaphthol complex in the presence of diisopropylethylamine (Scheme 51) [136]. Thermal decarboxylations of bicyclic lactones such as 68 are known to yield dienes which may undergo subsequent pericyclic reactions [137] thus, the adducts of this process are potentially useful chiral building blocks. The nature of the substituent on the 2k component was found to be crucial for the realization of high enantioselectivity. 

Evans et al. reported that in the presence of Cz-symmetric bis(oxazoline)—Cu(II) complex 438 the inverse electron demand hetero-Diels—Alder reaction of the a,/Tunsaturated carbonyl compounds 436 with ethyl vinyl ether gave the chiral dihydropyrans 437 in high diastereo- and enantioselectivities (Scheme 139).199c... 

Markd and Evans have used ytterbium triflate complexes of BINOL and found that vinyl sulfide (8.119) provided the highest enantioselectivity in the inverse electron demand Diels-Alder reaction with the diene (8.120). ... 

Swindell CS, Tao M (1993) Chiral Auxiliary-Mediated Asymmetric Induction in a Thermal Inverse Electron Demand Hetero-Diels-Alder Reaction - Enantioselective Synthesis of the Taxol A-Ring Side Chain. J Org Chem 58 5889... 

The Bode group have documented an NHC-catalyzed enantioselective synthesis of ester enolate equivalents with a,p-unsaturated aldehydes as starting materials and their application in inverse electron demand Diels-Alder reactions with enones. Remarkably, the use of weak amine bases was crucial DMAP (conjugate acid = 9.2) andN-methyl morpholine (NMM, conjugate acid pAa = 7.4) gave the best results. A change in the co-catalytic amine base employed in these reactions could completely shift the reaction pathway to the hetero-Diels-Alder reaction, which proceeded via a catalytically generated enolate. An alternative pathway that occurred via a formal homoenolate equivalent was therefore excluded. It is demonstrated that electron-rich imidazolium-derived catalysts favor the homoenolate pathways, whereas tri-azolium-derived structures enhance protonation and lead to the enolate and activated carboxylates (Scheme 7.71). 

Bode, et al. developed a highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral A-heterocyclic carbenes. Scheme 3.28 [43]. Reactions of alkyl fra -4-oxo-2-butenoate 80 with A-sulfonyl imines 81 and catalyst 82 (10-15 mol%), DIPEA (10 mol%) in toluene-THF (10 1) at room temperature afforded the dihydopyridinones 83 in excellent diastereo- and enantioselectivity (>50 1 cw-diastereoselectivity, 99% ee). The LUMO -controUed inverse electron demand Diels-Alder cycloaddition was facilitated by NHC-carbene catalyst 82. Similar reactions without the catalyst would require high pressure (12 bar) or high temperature. The high cw-diastereoselectivity which would arise from (Z)-enolate reacting with the dienophile is rationalized as depicted in Scheme 3.28. 

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