Diels-Alder macrocyclization

Remarkably, this complete regiocontrol was due to the sterical hindrance imposed by the chlorine substituent on the diyne 88 building block—and therefore the use of alkynyl chloride 88 turned out to be ideal for the regioselective assembly of the chlorobenzene moiety of sporolide B (94). The [2 + 2 + 2] cycloaddition product 91 was then transformed into the o-quinone 92 to prepare the second key step of this total synthesis, the thermally induced intramolecular Diels-Alder macrocyclization reaction (Scheme 7.20). 

Zapf, C.W., Harrison, B.A., Drahl, C., and Sorensen, E.J. (2005) A Diels-Alder macrocyclization enables an efficient asymmetric synthesis of the antibacterial natural product abyssomicin C. Angew. Chem. Int. Ed., 44, 6533-6537. 

A notable example of an intramolecular Diels-Alder cycloaddition reaction is found in Kishi s synthetic investigations that culminated in the total synthesis of pinnatoxin A (66, Scheme 17.12) [49]. The intriguing Diels-Alder macrocyclization was initiated when mesylate 64 was treated with DABCO and Et3N to form the corresponding diene. The cycloaddition that ensued gave 65, and subsequent deprotection and intramolecular imine formation completed the synthesis of pinnatoxin A (66), a shellfish toxin and Ca -channel activator. 

Thermal fragmentation of l,3-dioxin-4-ones or acylated Meldrum acids with generation of a-oxoketenes, hetero Diels-Alder reactions of the latter, and their transformations into lactones and lactams, among them macrocyclic 99YGK76. 

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]... 

Deslongchamps P. Transannular Diels-Alder Reaction on Macrocycles a General Strategy for the Synthesis of Polycyclic Compounds A Idrichimica Acta 199124 43-56... 

Thomas E. J. Cytochalasan Synthesis Macrocycle Formation Via Intramolecular Diels-Alder Reactions Acc. Chem. Res. 1991 24 229 235... 

Similar results were obtained for analogous complexes of the de-( er -butyl)ated macrocycle (L24)2-. The ter7-butyl substituents do not affect the regiochemistry of this particular Diels-Alder reaction, but they clearly increase its rate. The observed trend is indicative of a small stabilization of the transition-state by hydrophobic effects (AAG 3 kJ/mol k coinpiex/k l) lckgr(nin(i = expiAAG /RT)). This would be consistent with our earlier observation that complexes bearing less polar carboxylate anions have the higher stability constants (see Section III.E). 

The synthesis of the macrocycles 43 (Scheme 9) is an example of repetitive, highly stereoselective Diels-Alder reaction between bis-dienes 41 and bis-dienophiles 42, containing all oxo or methano bridges syn to one another. The consecutive inter- and intramolecular Diels-Alder reactions only succeed at high pressure. Obviously, both reactions are accelerated by pressure. The macrocycles are of interest in supramolecular chemistry (host-guest chemistry) because of their well-defined cavities with different sizes depending on the arene spacer-units. 

SCHEME 9. Repetitive Diels-Alder reactions in the synthesis of macrocycles having cavities of different size93-94... 

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. 

Comparable to the influence of such structural well-defined macrocycles, cell-free extracts55 as well as antibodies309,310 also show strong catalytic effects. Hence, the use of organic compounds, which are able to form micelles, being active in water and easy to handle could lead to new insights and unexpected results for catalytic Diels-Alder... 

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. 

Larsen, J., Rasmussen, B.S., Hazell, R.G. and Skrydstrup, T, (2004) Preparation of a novel diphosphine-palladium macrocyclic complex possessing a molecular recognition site. Oxidative addition studies. Chem, Commun., 202-203 Braunstein, P., Clerc, G. and Morise, X. (2003) Cyclopropanation and Diels-Alder reactions catalyzed by the first heterobimetallic complexes with bridging phosphinooxazoline ligands. New J. Chem., 27,68-72 Braunstein, P., Clerc, G., Morise, X., Welter, R. and Mantovani, G. (2003) Phosphinooxazolines as assembling ligands in heterometallic complexes. Dalton Trans., 1601-1605. 

Templates possessing two hydrogen bonding subunits bind two substrates forming a ternary complex in which the substrates are positioned so as to facilitate bond formation between them [5.64a]. In a related way, the rate and stereoselectivity of a bimolecular Diels-Alder reaction are substantially increased by binding both the diene and the dienophile within the cavity of a tris-porphyrin macrocycle [5.64b]. 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

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. 

Finally, a thia Diels-Alder reaction representing a less common cycloaddition type in natural product synthesis shall be discussed. Thus, Vedejs et al. have included such a cycloaddition into an elegant strategy aimed at the synthesis of macrocyclic [ll]-cytochalasans such as zygosporin E 7-76 [536-538]. Thus, release of the thioaldehyde 7-73 from its phenacyl sulfide precursor in the presence of the silyloxydiene 7-74 yielded 7-75 as 2 1 mixture with its C20 epimer. Fortunately, equilibration of this mixture raised the ratio up to 10 1. Several subsequent steps yielded the tetracyclic intermediate 7-77 cleavage of its thioether moiety then liberated the 11-membered macrocycle present e.g. in zygosporin E 7-76 (Fig. 7-16). 

Fig. 9a4) between cyclopentadiene and a C=C bond of the dumbbell-shaped part of the rotaxane. The dumbbell-shaped part contains two dicarbonyl stations (Fig. 9a3), one derived from fumaric acid (tram -CO-C H=CH-CO-. station 1), the other derived from succinic acid (—CO-CH2-CH2-CO-, station 2). The two diamide sites of the macrocycle can form four H-bonds with the two carbonyl groups of a given station (Fig. 9al for the interaction of the two carbonyl groups of fumaric-acid-derived station 1 with the four NH groups of the macrocycle through four H-bonds, see Fig. 9a2). Station 1 (derived from fumaric acid) has a tram C=C double bond due to its preorganization, this station interacts with the macrocycle better than the station 2. Consequently, the macrocycle is initially located at station 1 (Fig. 9a5). The Diels-Alder cycloaddition (80° C, 90% yield) of cyclopentadiene to the double bond of station 1 results in a mixture of diastereomers (Fig. 9a4) and causes displacement of the macrocycle from station 1 to station 2 (Fig. 9a6). The cycloaddition is reversible and the retro-Diels-Alder reaction occurs quantitatively (250°C, reduced pressure) when cyclopentadiene dissociates from the axle of the rotaxane this produces a displacement of the macrocycle from station 2 back to station 1. 

An interesting and rare example of inverse electron demand transannular Diels-Alder reaction of the furanophane 65 was employed for the synthesis of the chatancin core as depicted in Equation (45) <2003JOC6847>. The diastereoselectivity of this reaction was controlled by the macrocyclic conformation of 65 in the protic reaction medium. 

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