Cascade cycloaddition

Graening, T, Friedrichsen, W., Lex, J., Schmalz, H.G. (2002) FacUe Construction of the Colchicine Skeleton by a Rhodium-Catalyzed Cyclization/Cycloaddition Cascade. Angewandte Chemie International Edition, 41, 1524-1526. 

In contrast to the failure of Diels-Alder reactions, dipolar cycloadditions of indoles are much more successful, and the Boger group has reported a fascinating [4+2]/l,3-dipolar cycloaddition cascade involving indole as the dipolarophile in their impressive synthesis of vindoline (Scheme 4.8) [26]. After the initial... 

In an alternative approach to annulation across the indole 2,3-tt system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)-promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to ( )-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-tt bond to generate 149 <06OL3275>. 

A systematic exploration of a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was conducted in which the tethered initiating dienophile, the tethered... 

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

Finally, saturated oxazolo[3,2-tf]pyridine derivatives can also be accessed via a Pummerer cyclization-deprotona-tion-cycloaddition cascade from imidosulfoxides <1999JOC2038> or by a [3+2] cycloaddition of nonstabilized... 

An interesting palladium-catalyzed allene/azide incorporation and intramolecular 1,3-dipolar cycloaddition cascade to tetrazolo[5,l-tf]isoquinoline has been published by Grigg et al. <2005TL5899>. In the first step of the events, 3-bromo-6-iodobenzonitrile 105 was reacted with the allene/trimethylsilylazide system in the presence of palladium(O) catalyst to yield a coupling product 106 which under the reaction conditions applied (DMF, 70 °C for 24 h) gave 107. 

This strategy was applied to the total synthesis of ( )-cis- and ( )-trans-trikentrin A [159]. Treatment of 194 with acetic anhydride at 160 °C provided indole derivatives via an N-acylation-[4 + 2]-cycloaddition cascade. Deacylation afforded trikentrin A. 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

Pummerer reaction conditions was followed by cycUzation to isomilnchnone 292 and hence to cycloadduct 293, which loses water to form a-pyridone 294. Subsequent manipulation involving deoxygenation and debenzylation completed the synthesis. In similar fashion, the azaanthraquinone alkaloid dielsiquinone was synthesized for the first time. Also, the quinolizidine alkaloids ( )-lupinine and ( )-anagyrine, and the ergot alkaloid ( )-costaclavine were synthesized using this Pummerer cyclization-cycloaddition cascade of imidosulfoxides and isomiinch-nones. 

The tandem double intramolecular 4 + 3/3 + 2-cycloaddition of the nitroalkene (10) produced the nitroso acetal (11) in 77% yield. Further functional group manipulations allowed for the conversion to the partial core (12) of the complex polycyclic alkaloid daphnilactone B in high yield (Scheme 3).6 The tandem intramolecular 4 + 2/3 + 2-cycloaddition cascade of 1,3,4-oxadiazoles (13) to polycyclic adducts (14) was investigated by considering the tethered initiating dienophile, the tethered dipolarophile, the 1,3,4-oxadiazole C(2) and C(5) substituents, the tether lengths and sites, and the central heterocycle (Scheme 4).7... 

Chromans possessing a fused isoxazolidine moiety 505 can be accessed via a palladium-catalyzed allene insertion-intramolecular 1,3-dipolar cycloaddition cascade reaction between ( )-fV-(2-hydroxybenzylidene)methanamine oxide, allene, and aryl iodides. This process creates two rings, two stereocentres and a quaternary carbon centre in one-pot (Equation 210) <2002CC1754>. 

It is worthy of note that this reaction is still the subject of solid and productive interest, as shown by the following recent examples. Chiu has exploited a rhodium carbene-promoted intramolecular formation of a carbonyl ylid - cycloaddition cascade as the key reaction in the synthesis of the nucleus of the cytotoxic diterpenoids pseudolaric acids A and B [54]. Although the diastereoselectivity was preferential for the undesired isomer 64, use of Hashimoto s chiral rhodium catalyst Rh2(SBPTV)4 reversed the selectivity in favor of 65 (64 65, 1 1.4) [55] (Scheme 29). 

In the same vein, Schmalz has proposed a facile construction of the colchicine skeleton by a rhodium-catalyzed cyclization/cycloaddition cascade [56]. A TMS group has to be introduced on the alkyne moiety of 66 in order to avoid participation of the relatively acidic alkynyl hydrogen atom in undesired proton transfers. The resulting 6,7,7 of 67a and 67b architecture was assembled in a remarkably diastereoselective manner (14 1) and in satisfactory yield (Scheme 30). 

Tandem carbonyl ylide generation from the reaction of metallo carbenoids with carbonyl continues to be of great interest both mechanistically and synthetically. Effective carbonyl ylide formation in transition metal catalyzed reactions of diazo compounds depends on the catalyst, the diazo species, the nature of the interacting carbonyl group and competition with other processes. The many structurally diverse and highly successful examples of tetrahydrofuran formation cited in this mini-review clearly indicate that the tandem cyclization/cycloaddition cascade of metallo carbenoids has evolved as an important strategy in both carbo- and heterocyclic synthesis. 

A highly efficient synthesis of tricyclic amines in good yield (72-74%) via a novel cyclization/cycloaddition cascade utilizing a substrate in which a dipolarophile is tethered to... 

Rh(l)-catalyzed [2-I-2-I-2] cyclotrimerization of 1,6-diynes (e.g., 1391 and 1394) with monoynes (e.g., 1392) in combination with stereospecific Ag(i)-catalyzed aldimine (metallo)azomethine ylide — cycloaddition cascades affords rapid access to complex heterocyclic benzene derivatives 1393 and 1395 in one-pot processes with the generation of five new bonds, four stereocenters and three rings (Schemes 266 and 267) <2000T8967>. 

Scheme 21 Access to tricyclic isoxazolidines by an inter-intramolecular cross-coupling-cycloaddition cascade [81]...

SPS of isoxazolidines through 1,3-dipolar cycloaddition and their transformations have been reviewed <2005CSR507>. Isoxazolidines were also prepared by nitrone 1,3-dipolar cycloaddition on silica gel in solvent-free conditions under microwave irradiation <2001J(P1)452>. Fused polycyclic isoxazolidines were prepared via a multi-component palladium-catalyzed allene insertion-intramolecular 1,3-dipolar cycloaddition cascade <2002CC1754, 2005AGE7570>. 

A domino Knoevenagel/hetero-Diels-Alder cycloaddition cascade was developed by Tietze (96CR115) and has continued to attract considerable attention. For... 

The Denmark group has also developed several interesting variants of this sequence. For example, the intermolecular [4 + 2]/intramolecular [3 + 2]-cycloaddition cascade (98JOC1604, 97JA125, 97JOC7086) was used to construct several natural... 

Kappe and co-workers ° used Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds (e.g., 557) that mimic the putative receptor-bound conformation of dihydropyridine type calcium channel modulators (Fig. 4.165). 

Elliott GI, Fuchs JR et al (2006) Intramolecular Diels-Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles. J Am Chem Soc 128 10589-10595... 

Fuwa H, Sasaki M (2007) A new method for the generation of indole-2,3-quinodunethanes and 2-(A-alkoxycarbonylamino)-l,3-dienes. Intramolecular Heck/Diels-Alder cycloaddition cascade starting from acyclic a-phosphoryloxy enecarbamates. Chem Commun 2876-2878... 

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