Tandem cycloaddition reactions

Optimum conditions in the cmcial tandem cycloaddition reaction involved the addition of the bulky aluminum Lewis acid, MAPh, to a cooled (-78 °C) solution of the silyl species 101 and the enantiomerically pure vinyl ether 103 followed by slow warming to -15 °C over 14.5 h (Scheme 10-34). Nitroso acetal 104 was then obtained in good yield as an inseparable 27 1 mixture of diastereoisomers. The major product derives from... 

Odedra, A., Lush, S.-F., Liu, R.-S. (2007). Dicobaltoctacarbonyl-mediated synthesis of tricyclic 5,6-dihydropyran-2-one derivatives via tandem cycloaddition reaction between cis-epoxyaUcynes, a tethered olefin, and carbon monoxide. Journal of Organic Chemistry, 72, 567-573. 

SCHEME 1 Tandem cycloaddition reactions toward tetraquinanes. 

Diastereomers of 13 were separated before the cycloaddition reaction since only one isomer was expected to adopt the sterically less demanding conformation in the transition state while the other diastereomer would suffer from severe steric congestion. Both diastereomers of precursor 13 were treated with KHMDS and the propynyliodonium salt, 12. The tandem cycloaddition reaction of the substrate 13a, to our pleasant surprise, gave tetraquinane product 11 in 50% yield, while 13b did not yield any cycloaddition product. These results allowed us to determine the relative stereochemistry of 13a and 13b as depicted. The sequential formation of alkylidene carbene and the TMM diradical intermediates transformed the cyclopentane substrate with a linear chain into the tetracyclic compound (Scheme 4). The core stmcture... 

SCHEME 4 Tandem cycloaddition reaction toward a tetraquinane. 

SCHEME 7 Tandem cycloaddition reaction triggered by nucleophilic addition reaction. 

Though it was ideal to introduce the methyl group prior to the formation of tetraquinane skeleton, the tandem cycloaddition reaction of the methyl-containing substrate 36 did not produce any cycloaddition product. While the preliminary interpretation of this failure was that the TMM diyl cycloaddition reaction would be sensitive to the steric environment, it turned out that the initial cyclopropanation reaction was sensitive to the substitution patterns of the olefin in the substrate, as the alternative cycloaddition reaction route via TMM yielded the tetraquinane product (Scheme 9). 

SCHEME 13 The tandem cycloaddition reaction to form the tetraquinane. 

From the chiral epoxide 56, the TMM cycloaddition precursor 55 for construction of the tetraquinane stmcture was prepared in a straightforward manner. Oxidation of epoxy alcohol 56 by the Swem protocol followed by treatment with Bestmann-Ohira reagent (E) produced alkyne 70. Iron-catalyzed Sisr2 -type reaction of 70 afforded an allene moiety as a diastereo-meric mixture in a 1 1 ratio and this mixture was used in the next step without the separation of isomers. Allenyl alcohol 71 was protected as a TBDPS ether to give 0-silylated allene 72. Deprotection of the acetal of 72 was delicate as the allenyl moiety was not stable under acidic condition. Fortunately, treatment of 72 with p-toluenesulfonic acid monohydrate in presence of formaldehyde afforded aldehyde 73, and subsequent treatment with p-toluene sulfonyUiyrazide furnished the precursor 55 for the tandem cycloaddition reaction (Scheme 21). 

In summary, we have accomplished the first asynunetric total synthesis of crinipellin A along with the formal total synthesis of crinipellin B. The very unique tetraquinane core structure of crinipellins was constructed efficiently through a tandem cycloaddition reaction via TMM diyl. The absolute stereochemistry of crinipellins was also confirmed through our asymmetric total synthesis. 

The tricyclic 1,3-diazepines 3 are formed by the action of two molar equivalents of aromatic isocyanates on the bis(imino-A5-phosphane) 1 in toluene at 20 C for 16 hours in a tandem aza-Wittig [2 t 2]-cycloaddition reaction . No further details were reported.167... 

Inter [4 +2]/intra [3+2] This type of tandem reaction using nitroalkenes has been explored most extensively. Four subfamilies of tandem cycloaddition exist, which arise from the four different points of attachment of the dipolarophilic tether. They are defined as fused, spiro, and bridged modes, as depicted in Scheme 8.37.149... 

The synthesis of pyrrolizidine alkaloid (-)-rosmarinecine illustrates the power of the fused mode tandem cycloaddition, as shown in Scheme 8.40.180 The all-cA relationship at the three contiguous centers C(l), C(7), and C(7a) can be constructed in a single-pot reaction with correct stereochemistry but C(6) cannot. 

More recently, some examples of intramolecular Diels-Alder and tandem intramolecular Diels-Alder/l,3-dipolar cycloaddition reactions of especially designed 1,3,4-oxadiazole derivatives have been described (Scheme 3). The... 

The tandem intramolecular Michael addition and 1,3-cycloaddition reactions of the corresponding alkenyl oxime have been used for the synthesis of the tricyclic core of the alkaloid halichlorine (Scheme 2.232) (728). 

Intramolecular [3+ 2]-cycloaddition of six-membered cyclic nitronates was extensively studied by Prof. Denmark and coworkers for the tandem [4 + 2] [3 + 2] -cycloaddition reactions of nitroalkenes. Detailed considerations of this problem were summarized in two reviews (394a, b). Most data were comprehensively discussed in Reference 394b. It is unnecessary to repeat this information however, it is worthwhile to briefly review the available data. 

Tandem nucleophilic substitution-[2+3] cycloaddition reaction of 4-bromo- and 4-toluenesulfonyloxy aldehydes 77 with sodium azide in DMF at 50 °C affords excellent yields (>80%) of substituted pyrrolo[.2.3.4]oxatriazoles 78 (Scheme 8) <2002HAC307>. 

Itoh and coworkers111 carried out tandem [2 + 2 + 2]/[4 + 2] cycloadditions catalyzed by a ruthenium catalyst. The reaction of diyne 147 with excess norbomene 148 in the presence of ruthenium catalyst 153, for example, afforded 149. Adduct 150 either dissociated from the catalyst or reacted with another equivalent of norbornene. In the latter case, a ruthenium catalyzed Diels-Alder reaction occurred, affording hexacyclic adduct 152 via 151 (equation 43). Compounds 150 and 152 were obtained in yields of 78% and 10%, respectively. Both cycloaddition reactions proceeded with complete stereoselectivity. When 1,6-heptadiyne was used instead of 147, only trace amounts of a cycloadduct were obtained. Replacing norbornene by norbornadiene, which was expected to result in polymer formation, did not afford any adduct at all. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

The reaction of 1,4-diphenylbuta-l,3-diene (2) with trithiazyl trichloride (3) yields a bi(thiadiazole) (4), an isothiazoloisothiazole (5), a dithiazolothiazine (6), and two thiazin-odithiatriazepines (7) and (8) by 1,2-, 1,3-, and 1,4-cycloaddition reactions (Scheme 2). The bridged-mode (/3-tether) tandem inter-[4 -E 2]/intra-[3 -E 2] cycloaddition of (ii)-2-methyl-2-nitrostyrene (9) with 1-butoxypenta-1,4-diene (10) produces stable tricyclic nitroso acetals (11) which afford, after reduction and protection, highly functionalized aminocyclopentanedimethanol triacetates (12) (Scheme 3). ... 

Extension of the linkage to hve atoms as in 285 provides routes to pyrazolines or pyrazoles 286, or 1,2,4-triazoles 287, fused to a seven-membered ring. The products are potentially biologically active and examples have been reported for X=N (177-181), X = 0 (181-185) and for a pyrazolo fused analogue (186) and X = S (187). In some cases, [e.g., (183)], these reactions are accompanied by tandem intramolecular-intermolecular reactions leading to the formation of macrocycles (see the section Tandem Intermolecular-Intramolecular Cycloaddition Reactions). 

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