Chemoselectivity intramolecular cycloadditions

An intramolecular cycloaddition also occurred with 3-ylidenepiperazine-2,5-diones such as 124 or 125, obtained by Wittig-Horner-Emmons reaction from phosphonate 121 and aldehydes 122 or 123, respectively. The products of the Diels-Alder reaction are the bridged bicyclo[2.2.2]diazaoctane rings 126 and 127 that have been found in biologically active secondary metabolite such as VM55599 and brevianamide A. The different type of structures employed in this case requires a chemoselective reaction in order to produce the expected products as single diastereoisomers after 20 days (Scheme 18) <2001JOC3984>. 

While the perfluorinated acetates do prefer insertion, they are still capable of forming 1,3-dipoles and have demonstrated interesting effects on the regioselectivity of intramolecular cycloaddition reactions, presumably through Lewis acid-mediated effects on the dipolarophile [83]. Other chemoselectivity effects have been noted in the intramolecular cycloaddition reactions and may or may not be partially induced by conformation and sterics [84]. It was further demonstrated thaL when possible, O-H insertion is the predominant outcome over other types of insertion for rhodium]II)-car-benes, independently of the catalyst. However, cycloaddition reactions have been demonstrated to be hgand-dependent [85]. 

The most commonly employed diazenes, e.g., diethyl, bis(2,2,2-trichloroethyl), and di-/m-butyl diazenedicarboxylate, and 4-phenyl-3/7-1,2,4-triazole-3,5(4/7 )-dione, are commercially available. However, various new reagents or methods recently introduced for the preparation of specific diazenes from hydrazines can be successfully applied to other hydrazines. Especially important is the development of chemoselective methods for converting hydrazines to diazenes in the presence of unsaturated substrates, for example in intramolecular cycloaddition reactions (Section 7.2.10.3.10.2.), where either the (di)ene group and other functions present in the substrate are sensitive to the (oxidizing) reagent employed. 

Also lacking generality due to chemoselectivity problems are attempts at achieving intramolecular cycloadditions from a,(i)-diynes in the presence of iron carbonyls. An efficient two-stage intramolecu-... 

As with any modern review of the chemical Hterature, the subject discussed in this chapter touches upon topics that are the focus of related books and articles. For example, there is a well recognized tome on the 1,3-dipolar cycloaddition reaction that is an excellent introduction to the many varieties of this transformation [1]. More specific reviews involving the use of rhodium(II) in carbonyl ylide cycloadditions [2] and intramolecular 1,3-dipolar cycloaddition reactions have also appeared [3, 4]. The use of rhodium for the creation and reaction of carbenes as electrophilic species [5, 6], their use in intramolecular carbenoid reactions [7], and the formation of ylides via the reaction with heteroatoms have also been described [8]. Reviews of rhodium(II) ligand-based chemoselectivity [9], rhodium(11)-mediated macrocyclizations [10], and asymmetric rho-dium(II)-carbene transformations [11, 12] detail the multiple aspects of control and applications that make this such a powerful chemical transformation. In addition to these reviews, several books have appeared since around 1998 describing the catalytic reactions of diazo compounds [13], cycloaddition reactions in organic synthesis [14], and synthetic applications of the 1,3-dipolar cycloaddition [15]. 

A palladium-catalyzed intramolecular benzannulation of bis-enynes 1135 proceeds chemoselectively to afford dihydroisocoumarins 1136 (Equation 441) <2002JOC2653>. A reaction sequence involving ruthenium-catalyzed yne-ene cross-metathesis of a polystyrene supported undecynoic acid ester followed by a Diels-Alder cycloaddition reaction with DMAD provides the basis for a combinatorial approach to dihydroisocoumarins featuring a variety of side chains at C-6 and C-8 <1999SL1879>. 

As is the case with totally intermolecular cocycloadditions, chemoselectivity is a potential problem in partially intramolecular systems where the desired process, combination of a diyne with a monoyne, may face competition from cycloadditions involving either exclusively the diyne or exclusively the monoyne. In practice chemoselectivity is readily achieved. Phosphite complexes of Ni° chemoselectively catalyze rapid and efficient cycloaddition of alkynes to heteroatom-containing diynes in good yields (equation... 

Logothetis studied the thermal intramolecular azide-alkene cycloaddition (IAAC) of 5-azido-5-methyl-1-hexene and observed the formation of a mixture of imines and aziridines <65JA749>. The first case of utilization of silica gel in the selective decomposition of triazoline (35) to pyridines and aziridines (X = CH2—CH2, (CH2)3) was reported by Murthy and Hassner (Equation (17)) <87TL97>. The role of silica gel in the chemoselective reaction is still obscure, but it is likely that acidic surface... 

Comparable levels of stereocontrol were observed in the Rh2(MEPY)4-catalyzed lactonization in Eq. (41) (76% ee) competition from intramolecular aromatic cycloaddition reduced somewhat the chemoselectivity of the reaction [58]. 

Treatment of 762 with allyl bromide and sodium hydride provides in 82% yield the C2-symmetric pyrrolidine 776. Chemoselective N-oxidation with er butylhydroperoxide in the presence of vanadyl acetylacetonate affords in 75% yield the N-oxide 111 which, when treated with LDA, forms a benzylideneazomethine ylid (having the Z-configuration) that undergoes an intramolecular 1,3-dipolar cycloaddition to afford the e isolable product in 35% yield (Scheme 170). 

A Rh-catalyzed intramolecular [3 + 2 + 2] cycloaddition afforded synthetically relevant 5,7,5-fused tricyclic sy -cycloadducts from readily available dienyne precursors with high diastereo- and chemoselectivity (14CEJ10255). 

The need for the high reaction temperature has been a major obstacle in developing the tandem cycloadditions of 1,3,4-oxadiazoles. As a consequence, chemoselectivity of such processes is poor. Successfiil activafion of the [4 + 2] step in such a tandem process using high pressure or Lewis acids is unknown. Only highly symmetrical products could be prepared until recently via double intermolecular and itner-[4 + 2]/intra-[3 + 2] variants. The chemoselectivity of a double intramolecular variant of the tandem process is not plagued by these limitations and it has been employed in the syntheses of Vinca alkaloids and their analogs. 

---