Hetero-Diels-Alder reaction preparation

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

Several groups have reported the use of rare earth complexes as catalysts for asymmetric Diels-Alder reaction. Qian and Wang described thus the preparation and use of Yb complexes chelated by Pr-PyBOx to successfully achieve the hetero-Diels-Alder reaction of methyl glyoxylate with Danishefsky s diene in 77% ee and 73% yield (Scheme 37) [98]. 

Bolm et al. [108] prepared a C2-symmetric bis (sulfoximine) as ligand for the copper-catalyzed hetero-Diels-Alder reaction. The stereogenic sulfur atom being located near the AT-coordinating atom, these structures were assumed to be promising for asymmetric catalysis. Their Hgand (79 in Scheme 43) was synthesized by palladium-catalyzed N-aryl imination from 1,2-dibromobenzene and (S)-S-methyl-S-phenylsulfoximine with Pd2dba3 in 70% yield. 

Tocopheryl)propionic acid (50) is one of the rare examples that the o-QM 3 is involved in a direct synthesis rather than as a nonintentionally used intermediate or byproduct. ZnCl2-catalyzed, inverse hetero-Diels-Alder reaction between ortho-qui-none methide 3 and an excess of <2-methyl-C,<9-bis-(trimethylsilyl)ketene acetal provided the acid in fair yields (Fig. 6.37).67 The o-QM 3 was prepared in situ by thermal degradation of 5a-bromo-a-tocopherol (46). The primary cyclization product, an ortho-ester derivative, was not isolated, but immediately hydrolyzed to methyl 3-(5-tocopheryl)-2-trimethylsilyl-propionate, subsequently desilylated, and finally hydrolyzed into 50. 

The domino Knoevenagel/hetero-Diels-Alder reaction is a prominent example of the great advantage of domino processes as it not only allows the efficient synthesis of complex compounds such as natural products starting from simple substrates, but also permits the preparation of highly diversified molecules. Due to the vast number of reports that have been made, only a few recent publications can be discussed here, although several excellent reviews on this topic have been produced that provide a more detailed insight into this useful method [372]. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

An intramolecular hetero-Diels-Alder reaction of enantiomerically pure iV-acyl nitroso derivatives 78, prepared from hydroxamic acids 77 by oxidation on treatment with Pr4NI04 in an aqueous medium, afforded a mixture of diastereomeric pyrido[l,2-A][l,2]oxazin-8-ones 79 and 80 (Scheme 5) <1996J(P1)1113, 20000L2955,... 

The hetero Diels-Alder reactions discussed thus far use 2-10 mol% of catalyst. Jorgensen s group44b found that the reaction could be carried out even at very low catalyst loading. The catalyst can conveniently be prepared in situ by mixing the chiral ligand 83 and copper triflate in the reaction system. Scheme 5-35 shows that product 112 can be obtained with good yield and high enan-... 

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

The starting material was prepared with the modification on the epibatidine bicychc ring system by repositioning the nitrogen atom to a methylene group. We carried out the Hetero-Diels Alder reaction of cyclopentadiene and iminium ion generated from ammonium chloride and formaldehyde in the aqueous medium and protected resulted unstable secondary amine with benzoyl chloride to provide (3) in good yields [5] (Scheme 38.1). 

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 ). 

A method was developed for preparation of the tetracyclic carboline alkaloids iso-canthine, isocanthin-6-one and l-methylisocanthin-3-one by an intramolecular hetero-Diels-Alder reaction. For example, oxime 317 in sulfolane at 285 °C afforded isocanthine 318 in 8% yield (equation 137) . 

A difluorinated analogue of the Danishefsky diene has been prepared by reductive defluorination with Mg(0) of an a,/i-unsaturated trifluoromethylketone. Its use in a hetero-Diels-Alder reaction (including asymmetric version) can lead to oxygen- and nitrogen-containing heterocycles (Figure 2.25)." ... 

Starting from Fluoral Fluoral (trifluoroacetaldehyde) is an unstable gas that must be prepared before use by dehydration of the corresponding hydrate (commercially available). In spite of this limitation, fluoral itself has been used as a substrate in various reactions. Among the most recent examples, carbonyl-ene and hetero-Diels-Alder reactions deserve mention. The use of chiral Lewis acid... 

The second asymmetric synthesis deals with the preparation of a C-difluoromethyl iminosugar. The key step of this synthesis is a hetero-Diels-Alder reaction with a chiral imine of difluoroacetaldehyde (Figure 6.32). ... 

Inda-box ent-9a has been used recently in the production of the natural product (-)-malyngolide 265. " The key step of the synthesis by Ghosh and Shirai, as shown in Figure 9.80, is the hetero-Diels-Alder reaction of Danishefsky s diene 112 and cx-ketoester 263 to afford the pyranone derivative 264 in 77% yield and 47% ee that was converted into (—)-malyngolide in several additional steps. The preparation of different pyranones was investigated using different ot-ketoesters. 

An intramolecular hetero-Diels-Alder reaction of o-thiobenzoquinone methides, generated in situ from bis(2-formyl-phenyl)disulfide and alkenols in the presence of iodine, has been used to prepare thiochromans (Scheme 22) <2003TL6513>. 

An intramolecular hetero-Diels-Alder reaction has been used to prepare octahydro-14//-benzo[g]quinolino[2,3- 7]-quinolidines (Scheme 38) <1998BML2881>. The same researchers have published a major study on the mechanism of this hetero-Diels-Alder reaction and have shown that under Lewis acid-catalyzed conditions it proceeds via a stepwise mechanism <1996T955>. 

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