Diels-Alder reactions paracyclophanes

Cycloadditions of [2.2]Paracyclophane and its Analogs 3.3.1. Diels—Alder Reactions... 

Intramolecular Diels—Alder reactions without prior 1,4-addition of oxygen (cf. previous section) have similarly been postulated for a number of [2.2]paracyclophane analogs. When [2](2,5)furano[2](l,4)naphthalen-ophane (42) is heated in excess dimethyl acetylenedicarboxylate at 100 °C, a polycyclic compound of structure 134 is formed. The mechanism of formation of 134 is most probably as follows 101> the furan moiety reacts as active diene component in an intermolecular Diels—Alder reaction to give 135. This is followed by further intramolecular 1,4-addition with the unsubstituted naphthalene ring as diene component to give the product 133, which has been isolated. 

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). 

DIELS-ALDER REACTION OF 1,2,4,5-HEXATETRAENE TETRAMETHYL[2.2]PARACYCLOPHANE-4,5,12,13-TETR AC ARBOX Y LATE... 

Paracyclophanes Prepared by Diels-Alder Reaction of Disubstituted Acetylenes with 1,2,4,5-Hexatetraene13- 14... 

A different synthetic approach to benzoannelated [2.2]paracyclophanes was realized by the Diels-Alder reaction of bis (methylene) [2.2] paracyclophane (13) and tetrakismethylene[2.2]paracyclophane (15) with para-benzoquinone [20]. The bis(exomethylene)paracyclophane derivatives were obtained from 6 and 7 via a copper-mediated coupling with methyl magnesium bromide, bromination and debromination. The dienes 13 and 15 react readily to the bis- and tris-phanes 16 and 17 when heated with para-benzoquinone in dichlorobenzene. However, both compounds are extremely poorly soluble in organic solvents and... 

Scheme 5. Synthesis of benzoanellated [2.2]paracyclophanes via Diels-Alder reactions with para-benzoquinone [20]...

Most of the synthetic approaches towards benzoannelated [2.2]paracyclo-phanes use the Diels-Alder reaction to build up the annelated rings [18,22,29]. [2.2]Paracyclophane-l-ene (32) and [2.2]paracyclophane-1,9-diene (42) can be considered as the simplest dienophiles for this purpose. Since the first syntheses of these compounds in 1958 by Cram et al. [32], various attempts have been made to get them to react with dienes in terms of Diels-Alder reactions. However, [2 + 4] cycloadditions were never observed [33], and could not be facilitated either by the application of high pressure, or the presence of Lewis acid catalysts Diels-Alder adducts were not even obtained with dienes such as tetrachloro-thiophene dioxide, known for its high reactivity in [2 + 4] cycloadditions with an inverse electron demand. All the more surprising was the observation that monoene 32 reacts smoothly with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate at room temperature leading to a dihydropyridazine-annelated paracyclophane 39 in high yield [34a]. As reported for other tetrazine Diels-Alder reactions... 

Scheme 14. Diels-Alder reaction of [2.2]paracyclophane-l,9-diene (42)...

In addition, [2.2]paracyclophane was transformed into reactive bis-dienes. By reaction of the furan cycloadducts 49 with tetraphenylcyclopentadienone and thermal retro-Diels-Alder reaction [2.2](4,7)isobenzofuranophane 51 was obtained [38]. The highly reactive molecule was trapped in situ with para-ben-zoquinone. The more stable tetraphenylisobenzofuranophane 57 was synthesized via the classical procedure to [2.2]paracyclophanes of Hopf [39] the reaction of 1,2,4,5-hexatetraene 53 with dibenzoylacetylene 54 gave 4,5,12,13-tetra-benzoyl[2.2]paracyclophane (56), that was reduced and cyclized to the target molecule 57 [38]. 

Scheme 18. Synthesis of rigid ladder oligomers with [2.2]paracyclophane units by repetitive Diels-Alder reactions [43]...

If this evidence were not incriminating enough, additional substantiation for its likelihood was provided in 2002 by Professor Matthew Shair and two of his graduate students at Harvard University through the first chemical synthesis of longithorone A (1) predicated on these same Diels-Alder reactions. This accomplishment is the subject of this chapter, an achievement whose success ultimately relied not only on the power of [4- -2]-cycloadditions, but also on an inventive strategy to atropselectively construct both [12]-paracyclophanes at the heart of Schmitz biosynthetic hypothesis. 

SCHEME 16.38 Synthesis of [2.2]paracyclophane derivatives through Diels-Alder reaction of bis-allene. 

FIGURE 14.11 [7]Paracyclophane undergoes the Diels-Alder reaction at a lower temjterature than benzene. 

PROBLEM 14.3 Use an arrow formalism to show how [7]paracyclophane forms the product shown in Rgure 14.11 through a Diels-Alder reaction. 

Shair and co-workers turned their attention to the regiochemical outcome of enyne-metathesis macrocyclizations, and they completed the biomimetic synthesis of a cytotoxic marine natural product (—)-longithorone A (204, Scheme 24.51). Biosynthetically, the natural product has been proposed originating from two [12]-paracyclophanes 205 and 206 by two Diels-Alder reactions, and thus, the authors applied enyne metathesis macrocyclization to the preparations of paracyclophanes 205 and 206. Both metathesis precmsors 208 and 210 were prepared from the common intermediate 207. The cyclization of enyne 208 in the presence of [Ru]-Ia (50mol%) in refluxing CH2CI2 under ethylene atmosphere proceeded with excellent atropdiastereoselectivity and -stereoselectivity. On the other hand, the macrocyclization of enyne 210 was less atropdiastereoselective (selective formation of the endocy-clic olefin ( /Z= 3.9 1). Nevertheless, the desired product 211 was obtained in 31% yield. In the absence of ethylene, neither macrocyclization of 208 nor 210 occurred. 

Fig. 16 Preparation and reactions of diformyl[2.2]paracyclophanes. (a) formylation of dibromo [2.2]paracyclophanes (b) preparation of pseudogeminal diformyl[2.2]paracyclophane (c) Wittig and Bestmann-Ohira reactions of aldehydes to afford divinyl and diethynyl compounds, respectively (d) preparation of 4,5,12,13-substituted [2.2]paracyclophanes by Diels-Alder reaction between 1,2,4,5-hexatetrene and substituted alkynes (e) preparation of step tetrasubstituted compounds from 1,2-disubstituted ethynes...

An enantioselective biomimetic synthesis of (—)-longithorone A was accomplished on the basis of the proposed biosynthesis [llj. Two [12]-paracyclophanes 25 and 26 were synthesized from common intermediate 27 by applying ene-yne metathesis macrocyclization in 42 and 31% yields, respectively. Intermolecular Diels-Alder reaction of 25 and 26 provided 32. Deprotection followed by oxidation gave 33, which spontaneously gave longithorone A via transannular Diels-Alder reaction (Scheme 6.8). 

Diels-Alder additions with numerous dienophiles 283 lead to the conjugated tri-enes 320 [133], whereas the use of activated triple bonded dienophiles 321 (R1 = R2 = C02CH3i CN, CF3i etc. R1 = CHO, CN, COOCH3, etc., R2= H) constitutes the simplest route to functionalized [2.2]paracyclophanes, 322, the primary p-xyly-lene adducts dimerizing under the reaction conditions [134,135]. 

Paracyclophane[4,5-(/]oxazol-2(3/7)-one (152) exhibiting planar chirality has been used as chiral auxiliary in asymmetric Diels-Alder (DA) and Michael reactions via a,P-... 

M. Shair and co-workers were the first to apply the enyne metathesis for macrocyclization during the biomimetic synthesis of (-)-longithorone A." The two 16-membered paracyclophane building blocks, one diene and one dienophile component, were prepared using 50 mol% Grubbs s first-generation catalyst under 1 atm ethylene gas pressure. These components, after several additional steps, underwent two facile Diels-Alder cycloaddition reactions to afford the natural product. 

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