Macrocyclization using Diels—Alder reaction

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

Synthesis of sterically rigid macrocycles by the use of pressure-induced repetitive Diels-Alder reactions [84]... 

The use of porphyrinic ligands in polymeric systems allows their unique physio-chemical features to be integrated into two (2D)- or three-dimensional (3D) structures. As such, porphyrin or pc macrocycles have been extensively used to prepare polymers, usually via a radical polymerization reaction (85,86) and more recently via iterative Diels-Alder reactions (87-89). The resulting polymers have interesting materials and biological applications. For example, certain pc-based polymers have higher intrinsic conductivities and better catalytic activity than their parent monomers (90-92). The first example of a /jz-based polymer was reported in 1999 by Montalban et al. (36). These polymers were prepared by a ROMP of a norbor-nadiene substituted pz (Scheme 7, 34). This pz was the first example of polymerization of a porphyrinic macrocycle by a ROMP reaction, and it represents a new general route for the synthesis of polymeric porphyrinic-type macrocycles. 

An enantioselective biomimetic synthesis of longithorone A was accomplished on the basis of proposed biosynthesis. " The syntheses of two [12]-paracyclophanes 105 and 107 are realized by applying ene-yne metatheses macrocyclization to 104 and 106, which are synthesized from the common substrate 103. Longtholone A is constructed using intermolecular and transannular Diels-Alder reactions followed by oxidation (Scheme 40). 

The Diels-Alder reaction is an important and widely used reaction in organic synthesis (Sauer and Sustmann, 1980), and in the chemical industry (Griffiths and Previdoli, 1993). Rate enhancement of this reaction has been achieved by the use of solvents such as water, surfactants, very high pressure, lithium amides, alkylammonium nitrate salts, and macrocyclic hosts (Sherman et ak, 1998). Diels-Alder reactions can be ran in neutral ionic liquids (such as 1-butyl-3-methylimidazolium trifluoromethanesulfo-nate, l-butyl-3-methylimidazolium hexafluorophophate, l-butyl-3-methylimidazolium tetrafluoroborate, and l-butyl-3-methylimidazolium lactate). Rate enhancements and selectivities are similar to those of reactions performed in lithium perchlorate-diethyl ether mixtures. 

Macrocyclic azodicarboxylates containing a steroid skeleton were also synthe-tized using a similar synthetic route [52]. These compounds were trapped by Diels-Alder reaction with cyclopentadiene. 

Intramolecular Diels-Alder reaction can be used as a macrocyclization means. Thomas and Whitehead [167] apphed this approach to the synthesis of the 13-membered cytochalasan proxiphomin (280). As shown in Scheme 94, the long chain precursor 278 was heated in toluene at 100 °C for 5 h to give the 13-membered skeleton 279 and the endo adduct (52 48) in 52% yield. There are several other examples of the application of intramolecular Diels-Alder reaction to the synthesis of macrocyclic natural products [168]. 

In the first total synthesis of zygosporin E (1195), Vedejs et al. also utilized a.Diels-Alder reaction to form the isoindolone core (739), but used an alternative strategy for stereochemical control at the macrocycle. During the macrocycle construction, a sulfur functionality served as a tool for stereospecific introduction of ring substituents (756, 757). The zygosporin E (1195) route is outlined in Scheme 14.8. 

The first total synthesis of pinnatoxin A (104) was completed by Kishi s group in 1998 [67,68]. Their synthetic strategy is shown in Scheme 13. They planned to make the seven-membered iminium ring at the last stage, and the key macrocyclization was carried out by an intramolecular Diels-Alder reaction. Fragments 138-141 were coupled using the Nozaki-Hiyama-Kishi reaction, Juba coupling reaction etc. 

Receptors 25 and 26 were also amphfied from the same DCL when using ammonium cations as templates that are TSAs of a Diels-Alder reaction and of an acetal hydrolysis respectively [138, 139]. Kinetic experiments confirmed that both macrocycles are catalytically active (see Chapter 4 for a more detailed discussion). 

The Diels-Alder reaction between acridizinium bromide and cyclopentadiene is typically catalyzed by cage compounds. In a seminal paper by Otto et al. [18], selection of catalysts was performed using the reaction product as a suitable TSA to select macrocycles from a dynamic library. Exposure of the dynamic combinatorial library (DCLs) based on dithiol building blocks to the product (as TSA) leads to the selection and the amplification of two hosts among all the constituents of the dynamic library (Figure 4.6). The selected cage compounds were applied as catalysts in separate experiments and, indeed, compound 7 was demonstrated to catalyze the Diels-Alder reaction between the two substrates. The reaction rate was... 

The disconnections shown for (+)-brefeldin A suggest the use of an intramolecular cyclization to close the macrocycle. In fact, the cyclopentene was formed via an intermolecular PKR/retro-Diels-Alder sequence (82 goes to 83) to take advantage of the high reactivity of norbomadiene in the PKR. Furthermore, a new cyclopentenone is revealed by the retro-Diels-Alder reaction so that PKR product 84 is a synthetic equivalent for cyclopenta-dienone 85. 

The final type of intramolecular Diels-Alder reaction that finds wide use in natural product total syntheses is the transannular process. Danishefsky exploited the power of this transformation during an oxidative dearomatization/transannular Diels-Alder cascade in his synthesis of 11-0-debenzoyltashironin. Deslongchamps produced the tricyclic core of cassaine via a transannular intramolecular Diels-Alder reaction. The tricyclic c/5-decalin with appended macrocycle framework of superstolide A is also available using this strategy. Roush demonstrated the effectiveness of this approach by heating 140 in toluene to yield cycloadduct 141 that was transformed into superstolide A in four more steps. ... 

Vinylic substitution carbopaUadation can also be employed to synthesize dienes (Scheme 7). Bromide 44 and the protected allylic amine 45 efficiently couple to yield diene 46 stereoselectively.f Diene 46 has been used to build a C23-C29 fragment of the cytotoxic macrocycle iejimalide A (47). Diels-Alder reactions of dienes generated by similar reactions can also be envisioned to be useful in complex molecule synthesis. 

A new strategy for the predictable creation of new chiral centres and its application to the synthesis of sugars and macrocycles is presented in a review on the use of double asymmetric induction in the aIdol condensation, the Diels Alder cycloaddition, epoxidation and hydrogenation. Two approaches to the construction of appropriately functionalised six-carbon chains are outlined in a review on the dg novo synthesis of carbohydrates from achiral precursors (i), hetero-Diels Alder reaction with inverse... 

Winterfeldt and co-workers discovered that ergosterol acetate 35 can be used to prepare macrocycle 37 by Diels-Alder/retro-Diels-Alder reactions. Cycloaddition of ergosterol acetate 35 to propargylic aldehyde in the presence of tungsten hexachloride as a Lewis acid catalyst produced a.jS-unsaturated aldehyde 36. When it was heated in toluene, the macrocyclic benzaldehyde 37 was obtained in 85% yield (Scheme 16.5). This skeletal... 

Efficient synthesis of the medium- and macrocyclic substrates and the ability to predict the stereoselectivity are the prerequisites for successful application of transannular reactions. Whereas the development in organic synthesis in the past few decades has led to new methods for preparation of these cyclic compounds, systematic exploration of transannular reactions has been rare. Indeed, besides the Diels-Alder reactions, transannular reactions were mostly studied in isolated examples as part of method development of general, nontransannular transformations. However, with continued interests in this powerful strategy and significant advances in computational methods and hardware, which can be used to predict the stereochemical course of transannular processes with increasing accuracy, there is no doubt that innovative transannular transformations will continue to emerge and be used in applications with increasing sophistication and efficiency. 

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