Homo-Diels-Alder cycloadditions

The reaction of norbornadiene with diethyl diazenedicarboxylate affords a mixture of two 1 1 adducts 2 and 3 in approximately equal amounts25 one of the adducts 3 is produced by homo-Diels-Alder cycloaddition, as demonstrated by further conversion to quadricyclene, and the other is the oxadiazine 2, not previously identified. 

Nonetheless, there are a small number of systems that do mediate such [2 -i- 2 -t- 2] cycloadditions. With allenes as the alkene , cycloaddition with both acetylene and terminal alkynes proceeds regio-selectively to give 3,5-dimethylenecyclohexenes using Ni catalysts, and mostly 3,6-dimethylenecyclo-hexenes using Ni° catalyst precursors (equation 19). Norbomadiene undergoes so-called homo-Diels-Alder cycloaddition with both alkenes and a ynes in the presence of nickel catalysts. Further elaboration of this chemistry with alkynes but not alkenes has been described using a Co/Al catalyst system (equation 20). Attempts to produce cyclohexenes via all-intramolecular [2 + 2 + 2] cycloaddition of l,13-dien-7-ynes or 1,1 l-dien-6-ynes have been unsuccessful. ... 

Enantioselective homo-Diels-Alder cycloaddition can also be achieved with Co(II)/Zn catalysts chirally modified with amino acid derived phosphite ligands63, Stereoselective cycloaddition of norbornadiene has also been observed with enones64 to give the [2 + 2 + 2] adducts, while with dienes in the presence of chirally modified Co(II)/Et2AlCl catalysts optically active [4 + 2 + 2] adducts were obtained in up to 66% yield and 79% ee65. 

In addition to the assembly of various carbocyclic and heterocyclic six-membered ring assembly, nickel-catalyzed [2+2+2] homo-Diels-Alder cycloadditions have been illustrated using norbomadiene derivatives (Scheme 3-30). Electron-deficient dienophiles undergo cycloadditions with norbomadiene using catalysts prepared from Ni(cod)2 and PPI13. Chemical yields and exo-selectivities are both generally high in these processes. 

The nickel-catalyzed homo-Diels-Alder cycloaddition with norbornadienes and electron-deficient alkenes is an effective method for generating strained polycyclic compounds. At the time of writing, this method is the only strategy for carrying out a nickel-catalyzed [2+2+2] cycloaddition with three alkene Jt-systems such that six contiguous stereocenters may be generated. Both acyclic and cyclic enones participate in the process (Scheme 80). 

Recent advances in the catalytic 2- -2 + 2-cycloadditions of alkenes, alkynes, and nitriles for the synthesis of carbo- and hetetro-cycles have been reviewed. Propar-gylic oxanorbornadiene esters (87) undergo facile intramolecular 2- -2- -2-homo-Diels-Alder cycloaddition in polar solvents (Scheme 27). ... 

Our overall objective is to explore the utility of the [2ti + 2tc + 2%] (homo Diels-Alder) cycloaddition reactions of norbomadiene as a route to synthesizing linearly and angularly fused polycyclic natural products... 

Let us now examine the Diels-Alder cycloaddition from a molecular orbital perspective Chemical experience such as the observation that the substituents that increase the reac tivity of a dienophile tend to be those that attract electrons suggests that electrons flow from the diene to the dienophile during the reaction Thus the orbitals to be considered are the HOMO of the diene and the LUMO of the dienophile As shown m Figure 10 11 for the case of ethylene and 1 3 butadiene the symmetry properties of the HOMO of the diene and the LUMO of the dienophile permit bond formation between the ends of the diene system and the two carbons of the dienophile double bond because the necessary orbitals overlap m phase with each other Cycloaddition of a diene and an alkene is said to be a symmetry allowed reaction... 

According to frontier molecular orbital theory (FMO), the reactivity, regio-chemistry and stereochemistry of the Diels-Alder reaction are controlled by the suprafacial in phase interaction of the highest occupied molecular orbital (HOMO) of one component and the lowest unoccupied molecular orbital (LUMO) of the other. [17e, 41-43, 64] These orbitals are the closest in energy Scheme 1.14 illustrates the two dominant orbital interactions of a symmetry-allowed Diels-Alder cycloaddition. 

Nickel-catalyzed [27t + 27t + 27r] (homo-Diels-Alder) and [27r-i-27r] cycloadditions of bicyclo[2.2.1 ]hepta-2,5-dienes [96]... 

Diels-Alder cycloadditions involving norbomene 57 [34], benzonorbomene (83), 7-isopropylidenenorbomadiene and 7-isopropylidenebenzonorbomadiene (84) as dienophiles are characterized as inverse-electron-demand Diels-Alder reactions [161,162], These compounds react with electron-deficient dienes, such as tropone. In the inverse-electron-demand Diels-Alder reaction, orbital interaction between the HOMO of the dienophile and the LUMO of the diene is important. Thus, orbital unsymmetrization of the olefin it orbital of norbomene (57) is assumed to be involved in these top selectivities in the Diels-Alder cycloaddition. 

Most metal mediated [2 + 2 + 2] cycloadditions involve two triple bonds which coordinate to a metal center to form a reactive metallocyclopentadiene species (vide infra). The corresponding reactions involving at least two double bonds and an intermediate met-allocyclopentane species are almost completely limited to norbornadiene systems. These reactions can be considered as homo Diels-Alder reactions. 

Fig. 6.2. HOMO-LUMO interactions rationalize regioselectivity of Diels-Alder cycloaddition reactions.

It was Woodward and Hoffmann who first introduced organic chemists to the idea that so-called frontier orbitals (the HOMO and LUMO) often provide the key to understanding why some chemical reactions proceed easily whereas others do not. For example, the fact that the HOMO in cw-1,3-butadiene is able to interact favorably with the LUMO in ethylene, suggests that the two molecules should readily combine in a concerted manner to form cyclohexene, i.e., Diels-Alder cycloaddition. 

A combined system formed from Co(acac)3, 4 equiv of diethylalu-minum chloride, and chiral diphosphines such as (S,S)-CHIRAPHOS or (/ )-PROPHOS catalyzes homo-Diels-Alder reaction of norbomadiene and terminal acetylenes to give the adducts in reasonable ee (Scheme 109). Use of NORPHOS in the reaction of phenylacetylene affords the cycloadduct in 98.4% ee (268). It has been postulated that the structure of the active metal species involves noibomadiene, acetylene, and the chelating phosphine. The catalyzed cycloaddition may proceed by a metallacycle mechanism (269) rather than via simple [2+2 + 2] pericyclic transition state. 

The Homo Diels-Alder Reaction of Norbomadiene with Acetylenes. [2 + 2+2] Cycloadditions of dienes such as norbomadiene with the double bonds in 1,4-position are called homo Diels-Alder reactions. Using an in situ catalyst (consisting of Co(acac)3-Et2AlCl-bis(diphenylphosphino)ethane) the products obtained with monosubstituted acetylenes, such as phenyl, i-propyl-, n-butyl-, t-butyl-, and trimethylsilylacetylene, are 4-substituted deltacyclenes. - In the formation of the polycyclic deltacyclene skeleton, six new stereo centers are generated in one step. Thus enantiocontrol by using optically active phosphine ligands as cocatalysts allows the synthesis of optically active cycloadducts, as shown for the reaction of norbomadiene with phenylacetylene to give 4-phenyldeltacyclene (eq 1). 

Two homo Diels-Alder reactions and a hetero Diels-Alder reaction, each using a silyloxydiene, have been used in a total synthesis of vinemycinone methyl ester (236) by Danishefsky (84JA2453 85JA1285). Ketoaldehyde 231, prepared by two Diels-Alder cycloadditions, reacted with diene 230 in chloroform in the presence of Eu (fod)j to produce the silyl enol ether... 

The more or less accidental discovery that fluorinated y9-diketonates of europium both effect the Lewis acid catalysis of Diels-Alder reactions [10] and interact with carbonyl functionalities of the substrates [102] emerged in a very prolific research. Despite the ready feasibility of homo-Diels-Alder reactions [103], hetero-Diels-Alder cycloadditions are preferentially mediated [104]. The endo select vities... 

The homo-Diels-Alder reaction is the thermally allowed [27ts -f 2ng -l- 2jts] cycloaddition, which results in the formation of a cyclopropane. ... 

Some related processes, such as the extended homo-Diels-Alder reaction (e.g. [lug + lug -I- 47Ts] cycloadditions), and the homocheletropic reactions, will also be discussed. 

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