Diels cycloisomerization

Palladium catalyzed cycloisomerizations of 6-cn-l-ynes lead most readily to five-membered rings. Palladium binds exclusively to terminal C = C triple bonds in the presence of internal ones and induces cyclizations with high chemoselectivity. Synthetically useful bis-exocyclic 1,3-dienes have been obtained in high yields, which can, for example, be applied in Diels-Alder reactions (B.M. Trost, 1989). 

One productive facet of Pd-catalyzed domino reactions is the cycloisomerization of enynes and allenes, as shown by Trost and coworkers [19]. Thus, transformation of the dienyne 6/1-10 using Pd(OAc)2 led to 6/1-13 in 72% yield, in which the last step is a Diels-Alder reaction of the intermediate 6/1-12 (Scheme 6/1.2). 

A novel use of Buchwald s titanium-based Alder-ene protocol is the cycloisomerization of dienynes to allenes (Equation (47)). Somewhat surprisingly, the Diels-Alder product was observed in trace amounts only in the cycloisomerization of amine 76. 

Weinreb86 has reported the Alder-ene cyclization of enallenes under thermal conditions (Equation (85)). Varying the substitution pattern of alkene and allene groups had little effect on the yield of cyclized product. One exception was a,/ -unsaturated ester 130(Equation (86)) cycloisomerization under thermal conditions led to the formation of the Alder-ene product 131 and the unexpected hetero-Diels-Alder product 132 in a 3 1 ratio. 

Scheme 27. Domino Heck-Diels-Alder reaction and formation of dendralenes by cycloisomerization of enediynes...

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

Cycloisomerization represents another approach for the construction of cyclic compounds from acyclic substrates, with iridium complexes functioning as efficient catalysts. The reaction of enynes has been widely studied for example, Chatani et al. reported the transformation of 1,6-enynes into 1-vinylcyclopentenes using [lrCl(CO)3]n (Scheme 11.26) [39]. In contrast, when 1,6-enynes were submitted in the presence of [lrCl(cod)]2 and AcOH, cyclopentanes with two exo-olefin moieties were obtained (Scheme 11.27) [39]. Interestingly, however, when the Ir-DPPF complex was used, the geometry of olefinic moiety in the product was opposite (Scheme 11.28) [17]. The Ir-catalyzed cycloisomerization was efficiently utilized in a tandem reaction along with a Cu(l)-catalyzed three-component coupling, Diels-Alder reaction, and dehydrogenation for the synthesis of polycyclic pyrroles [40]. 

The intramolecular Alder-ene reaction (enyne cydoisomerization reaction) with alkynes as the enophiles has found wide application compared with diene systems. The reason may be the ready chemo-differentiation between alkene and alkyne functionality and the more reactive alkyne moiety. Furthermore, the diene nature of the products will promote further applications such as Diels-Alder reactions in organic synthesis. Over the past two decades the transition metal-catalyzed Alder-ene cycloisomerization of l,n-enynes (typically n= 6, 7) has emerged as a very powerful method for constructing complicated carbo- or heterocydic frameworks. The transition metals for this transformation indude Pd, Pt, Co, Ru, Ni-Cr, and Rh. Lewis acid-promoted cydoisomerization of activated enynes has also been reported [11],... 

JV-Tosyl-l,2,3,4-tetrahydropyridines 208, which have at the 4-position a tethered electron-deficient alkyne, undergo metal-catalyzed cycloisomerization to give 2-azahydrindans 209, which can undergo Diels-Alder reactions with acroleins to give highly functionalized 1-azadecalins 210 (Scheme 55) <20040L5023>. 

Silver salts or reagents have received much attention in preparative organic chemistry because they are useful catalysts for various transformations involving C-G and C-heteroatom bond formation.309 Especially, the silver(i)/ BINAP (2,2 -bis(diphenylphosphino)-l,T-binaphthalene) system is a very effective catalyst for a variety of enantio-selective reactions, including aldol, nitroso aldol, allylation, Mannich, and ene reactions. Moreover, silver salts are known to efficiently catalyze cycloisomerization and cycloaddition reactions of various unsaturated substrates. Recently, new directions in silver catalysis were opened by the development of unique silver complexes that catalyze aza-Diels-Alder reactions, as well as carbene insertions into C-H bonds. 

Scheme 16 Synthesis of tricyclic systems by cycloisomerization of enynes and subsequent Diels-Alder reaction [69-72]...

Scheme 17 All-intramolecular domino cycloisomerization-Diels-Alder reactions [67-69]...

Trost and co-workers have applied enyne cycloisomerizations to the synthesis of a variety of natural products. In an early example, 1,3-diene 106 was efficiently prepared by cyclization of enyne 105 (Scheme 6-18). Diels-Alder elaboration of a relative of 106 and... 

As 1,/2-alkenes, 1,6-derivatives are used very frequently leading to five-membered heterocycles, while the use of 1,7-derivatives, which produce six-mem-bered heterocycles, is very rare. The reactions of 1,6-dienes, -enynes, and -diynes are classified into three groups (a) cycloisomerization, (b) tandem addition— cyclization, and (c) cycloaddition, such as the Pau-son—Khand reaction, cyclotrimerization, and the Diels—Alder reaction (Scheme 15).97 In these reactions five-membered heterocycles are constructed upon the carbon—carbon bond-forming processes. 

Finally, a few other recent developments in the area of m ramolecular alkyne cyclocoupling should be mentioned because of their considerable synthetic value, although the involvement of alkyne complexes is uncertain. These include Livinghouse s Rh-catalyzed Diels-Alder reactions [HO]. Negishi s stoichiometric Zr-promoted bicyclization of ene-ynes [97] (Scheme 4-32), and Tl-ost s Pd-catalyzed cycloisomerization of ene-ynes [111] (Scheme 4-33). 

The Feist-Benary and Paal-Knorr syntheses are commonly employed in the preparation of furan ring systems. In special cases where furan derivatives are difficult to prepare by other methods, Diels-Alder and retro-Diels-Alder reactions have become important methods for their synthesis. Finally, transition metal-catalyzed cyclization and cycloisomerization reactions have recently gained significant attention for their utility in the synthesis of highly functionalized furans. Key examples of these syntheses are highlighted in the sections below. 

Cycloisomerization of Diels-Alder adducts Cage compds. 

An interesting possibility for the construction of bicyclic systems containing one six-membered ring arises when an intramolecular Heck reaction or palladium-catalyzed enyne cycloisomerization [311] to give a vicinal exodimethylenecy-cloalkane is immediately followed by a Diels-Alder reaction (Scheme 8.15 and Scheme 8.19). This sequence is normally conducted in two steps, but may also... 

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