Diels-Alder reactions, hetero-, natural

The application of the hetero-Diels-Alder reaction to natural product synthesis has been reviewed. ... 

A review of cycloaddition reactions in carbohydrate chemistry is presented. The use of carbohydrate-derived dienes and dienophiles in the Diels-Alder reaction, hetero-Diels-Alder and dipolar addition reactions of carbohydrates are described. Stereochemical aspects of the cycloaddition processes are also discussed, and applications to the synthesis of natural products are included for each reaction type. Much of the material presented has appeared in the literature within the past five years however, earlier studies are also included in order to give a more representative historical perspective. 

Streith J., Defoin A. Hetero Diels-Alder Reactions With Nitroso Dienophiles Application to the Synthesis of Natural Product Derivatives Synthesis 1994 1107-1117 Keywords chiral dienes, chiral nitroso dienophiles... 

Tietze L. F. Domino-Reactions the Tandem-Knoevenagel-Hetero-Diels-Alder Reaction and Its Application in Natural Product Synthesis J. Heterocycl. Chem. 1990 27 47-69... 

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]. 

Another class of alkaloids recently synthesized by Tietze and coworkers using a three-component domino Knoevenagel/hetero-Diels-Alder reaction included the Ipecacuanha alkaloids such as emetine (2-798) [402], and the Alangium alkaloids such as tubulosine (2-799) [403]. Both types belong to the group of tetrahydroi-soquinoline alkaloids, and are formed in Nature from dopamine and the monoter-... 

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... 

As with all-carbon Diels-Alder reactions, the hetero-Diels-Alder reaction [41] can also be used as the first step in many combinations with other transformations. In contrast to the normal Diels-Alder reaction, several examples are known where the first step is followed by a 1,3-dipolar cycloaddition. This type of domino reaction has been especially investigated by Denmark and coworkers, and used for the synthesis of several complex natural products. Since Denmark has reviewed his studies in... 

Hetero Diels-Alder reactions using nitroalkenes followed by 1,3-dipolar cycloadditions provide a useful strategy for the construction of polycyclic heterocycles, which are found in natural products. Denmark has coined the term tandem [4+2]/[3+2] cycloaddition of nitroalkenes for this type of reaction. The tandem [4+2]/[3+2] cycloaddition can be classified into four families as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respectively.149 In general, electron-rich alkenes are favored as dienophiles in [4+2] cycloadditions, whereas electron-deficient alkenes are preferred as dipolarophiles in [3+2] cycloadditions. 

For the generation of several contiguous chiral centers, two alternative key step reactions can be applied (i) stereoselective CC-bond formation and (ii) stereoselective functionalization of compounds having already the required carbon skeleton. In the de novo-synthesis of carbohydrates and related natural products via inverse-type hetero-Diels-Alder reactions both of these principles are especially well documented as will be shown below (8-10). ... 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

Tietze LF (1990) Domino-reactions - the tandem-Knoevenagel-hetero-Diels-Alder reaction and its application in natural product synthesis. J Heterocycl Chem 27 47-69... 

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 ). 

Figure 9.39. Natural products via enantioselective hetero-Diels-Alder reactions.

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. 

The hetero-Diels-Alder reaction of homochiral camphor-derived thiabutadienes has given, for the first time, optically active bornene ring-fused dihydrothiopyrans with high diastereoselectivity (Scheme 53) <2000H(53)1685>. The exo endo- t2X o varied with the nature of substituent, varying from 91 9 (X = CH2, R = R = H) to 1 99 (X = CO,... 

R. R. Schmidt, Hetero-Diels-Alder reactions in highly functionalized natural product synthesis, Acc. Chem. Res. 19 250 (1986). 

The diversity of the products obtained by the three-component domino-Knoevenagel-hetero-Diels-Alder reaction can be further increased by a different work-up of the formed cycloadduct 141. Thus, hydrogenolytic removal of the Cbz-group in 141 led to 151 with a lactam and an aldehyde moiety by reaction of the formed secondary amine with the lactone moiety followed by elimination of benzyl alcohol. Reduction of 151 with lithium aluminum hydride gave benzoquinolizidine 152 (Scheme 5.30). Alkaloids of this type have so far not been found in nature, but it can be assumed that they might exist, since they could easily be formed from deacetylisopecoside 153, which is an intermediate in the biosynthesis of emetine 111. 

The stereocontrolled synthesis of a-hydroxyakylated piperidines, a motif frequently encountered in natural products, represents a difficult synthetic challenge that was recently tackled by Hall and co-workers using the aza-variant of the Vaultier-Lallemand three-component reaction described in Scheme 12.14 [62]. One interesting feature of this reaction is the use of hydrazines, as masked amines, which allows the hetero-Diels-Alder reaction to operate on a normal electron demand manifold. Toure and Hall recently applied this powerful MCR to the asymmetric synthesis of (—)-methyl dihydropalustramate 192 [91], a degradation product and postulated biosynthetic precursor of (+)-palustrine (Scheme 12.27) [92]. 

Although the reactions of carbonyl compounds with dienes follow a stepwise addition, the overall stereochemical outcome mimics that of the Diels-Alder reaction.1 2 5 242-244 The products of the hetero Diels-Alder reaction have been used as substrates for a wide variety of transformations and natural products syntheses.242,245-258 Many hetero Diels-Alder reactions use chiral auxiliaries or catalysts that have been successful for the Diels-Alder reaction. 

A hetero Diels-Alder reaction of a precursor 1-9 may be involved in the biosynthesis of the lignane carpanone 1-8 (Fig. 1-3), however, there is no proof for such an assumption [32]. On the other hand, it is well known that pericyclic reactions such as electrocyclic reactions and sigmatropic rearrangements occur in nature e.g. in the biosynthesis of vitamine D, vitamine B12 [33-35] and ecto-carpene [36]. 

Cyclic nitrones generated by [4+ 2]-cycloaddition of nitroalkenes undergo various, synthetically very valuable reactions. Thus, Denmark et al. have developed an elegant access to different enantiopure, 3- and 3,4-substituted pyrrolidine derivatives by reductive ring contraction of the cyclic nitrone resulting from a hetero Diels-Alder reaction [389,390]. Upon reaction of -2-nitrostyrene 4-51 with the chiral enol ether 4-52 in the presence of the bulky Lewis acid MAPh (4-53), three diastereomeric cycloadducts 4-54, 4-55 and 4-56 were formed. Hydrogenolysis of the main product 4-54 yielded the desired pyrrolidine 4-57 in excellent optical purity and allowed nearly quantitative recovery of the chiral auxiliary (Fig. 4-12) [391]. It is noteworthy that the nature of the Lewis acid catalyst, especially its steric demand, decisively influences the stereochemical course of such cycloadditions [392]. 

Natural Product Syntheses by Hetero Diels-Alder Reactions... 

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