Construction of Polycyclic Systems

The previous sections described a one-step methodology of the regiose-lective synthesis of benzene and some condensed polycyclic compounds on the basis of reactions of [2- -2- -2] and [4- -2] cycloaddition using acetylenic blocks. In this section the synthetic routes to a wide range of 

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This seminal concept for the construction of polycyclic systems, developed by Paquette and coworkers, is highlighted by the conversion of product (270) into dodecahedrane. "... 

Additions of (478) to furans which contain an appropriately placed aryl or vinyl bromide unit permit the construction of polycyclic systems by a Diels-Alder/radical cyclization/aromatization sequence (Scheme 116). ... 

We recently reported (1) a new approach to the stereoselective construction of polycyclic systems, illustrated by the cyclozirconation/carbonylation (2) of a computationally designed diene 1 (Scheme 1) to give the tetracyclic ketone 2. Ketone 2 was converted over several steps to (-)-androst-4-ene-3,16-dione (3). 

Hart and Ghosh [43] have explored the 7-exo aryl and vinyl radical cyclizations for the construction of polycyclic systems as part of their tandem cycloaddition-radical cyclization strategies for polycycles. Treatment of the bromides 177-179 with BujSnH and AIBN furnished the tetra- and pentacyclic compounds 180-182 via stereoselective 7-exo trig cyclizations. 

The major application of arynes in synthesis is in the construction of polycyclic systems using either the Diels-Alder or intramolecular nucleophilic addition reactions. 

Chart 3 summarizes the remarkable versatility and broad synthetic utility exhibited to date by the intramolecular addition of allylsilanes to conjugated dienones for the preparation of bicyclic systems. The use of this methodology for the stereospecific construction of polycyclic systems is presently in its infancy. However, in light of the remarkable versatility and broad syndietic utility demonstrated to date, this area will undoubtedly be the subject of continued interest. 

The application of nonenzymic biogenetic-like olefinic cyclizations for the stereospecific construction of polycyclic systems, developed by W. S. Johnson and his school, represents an exciting new approach to steroid total synthesis. The synthesis of progesterone, outlined below, is based on the finding that an appositely placed acetylenic bond participates in polyolefinic cyclizations directly to produce the C/D trans-fused hydrindane system... 

Closely related to the polyepoxide cascade procedure for the synthesis of polycyclic systems is Corey s biomimetic-type, nonenzymatic, oxirane-initiated (Lewis acid-promoted) cation-olefin polyannulation. By this strategy, compound 96, containing the tetracyclic core of scalarenedial, was constructed by exposure of the acyclic epoxy triene precursor 95 to MeAlCl2-promoted cyclization reaction conditions (Scheme 8.25) [45]. 

In Holton s and Wender s work, the total synthesis was achieved by sequentially forming the AB ring through the fragmentation of epoxy alcohols derived from (—)-camphor and a-pinene. Nicolau s, Danishefsky s, and Kuwa-jima s total syntheses involved B ring closure connecting the A and C rings, whereas in Mukaiyama s synthesis, the aldol reaction was extensively applied to construct the polycyclic system. 

Intermolecular and intramolecular photocycloaddition and photoaddition to aromatic rings in the electron-donor and electron-acceptor systems were discussed in this chapter. The highly stereoselective and regioselective photocycloaddition is a synthetically useful method for the construction of polycyclic carbon-skeleton compounds, including natural products. New aspects for the stereoselective intermolecular and intramolecular photocycloaddition reactions via exciplexes in less... 

The MCI cyclopentene annulations proceed with moderate efficiency and have been utilized for the construction of polycyclic molecules with fused, spiro and tethered ring systems (e.g. equations 118-120)28. With bis(phenyliodonium) diyne salts, biscyclopentene annulations are observed (e.g. equation 121)86. 

A selective sampling of the photochemical cycloaddition and cyclization chemistry of 2H-azirines has been outlined in this chapter. Some photochemical sequences increase molecular complexity more than others, but each seems to provide complex heterocyclic structures in a very efficient manner. Indeed, many of these photoreactions rapidly construct hetero-polycyclic systems that are difficult to produce in other ways. In contrast to their photochemical behavior, the major thermal reaction of 2H-azirines generally involves C(2)-N bond cleavage to form vinyl nitrenes which further react by either insertion into an adjacent C-H bond or else undergo addition across a neighboring rc-bond. The 27i-electrons of the carbon-nitrogen double bond of 2H-azirines can also participate in thermal symmetry-allowed [4- -2]-cycloadditions with a variety of substrates. It is clear from the above discussion that the chemistry of 2H-azirines is both mechanistically complex and... 

Corey s analysis to) of polycyclic systems and strategic bond disconnections directed by maximizing simplification of intermediates is an example of the definition of new heuristics for skeletal dissection ( 6). This analysis directs the selection of particular bonds for construction. His rules also derive in part from stereochemical considerations ( 7). A further treatment of rules for bond selection via stereochemistry would be valuable. 

This study showed that the lithium- and nickel-mediated formation of carbon-carbon bonds has considerable promise for the rational construction of polycyclic aromatic nuclei. Not only can such aromatic systems be elaborated... 

Alkenyl-lithiums, which can be prepared by metal-halogen interchange between an appropriate iodide and t-BuLi at — 78°C, undergo cyclizations on warming to room temperature before quenching with a proton source (equation 117) . This cyclization reaction has been extended for the construction of polycyclic alkanes by sequential polyolefinic cyclizations (tandem cyclizations). A propellane system could be constructed in a single step from his-intramolecular cyclization as shown in equation 118 . 

Hong BC, Shr YJ, Liao JH (2002) Unprecedented microwave effects on the cycloaddition of fulvenes. A new approach to the construction of polycyclic ring systems. Org Lett 4 663-666... 

Diels-Alder cycloaddition provides one of the most useful methods for the construction of polycyclic aromatic ring systems. With the use of maleic anhydride as dienophile, two additional carbon atoms may be fused to the bay region sites of some polycyclic arylenes to generate additional rings. For example, the first step in the synthesis of benzo[ghi]perylene 6 involves a Diels-Alder cycloaddition between perylene and maleic anhydride (Scheme 3.5) [19]. Aryne intermediates generated in situ also serve as dienophiles for Diels-Alder cycloadditions for example, reaction of 1,5-naphthadiyne (generated in situ from 2,6-dibromo-l,5-bis[(p-tolylsulfonyl)oxy] naphthalene with 2-methylisoindole forms an adduct which upon oxidation with m-chloroperbenzoic acid affords dibenzo[fe,k]chrysene 7 (Scheme 3.5) [20]. 

Several examples have recently appeared which demonstrate the utility of the intramolecular Diels-Alder reaction for the construction of heterocyclic systems. Oppolzer has established that thermally generated quinodimethanes will undergo intramolecular Diels-Alder reactions to produce polycyclic amides (e.g., 26 ). The required amides of the type 26 are readily obtainable from benzocyclobutanecarbo Qrlic acid. This method has been applied to the total synthesis of the alkaloid dl-chelido nine. 

In 2009, Cai et al. reported a cascade olefin cross-metathesis/intramolecular Friedel-Crafts alkylation for the construction of polycyclic indoles 133 (Scheme 5.89) [90], A Ru complex (134)/chiral Brpnsted acid [(S)-135] binary system was used in this relay catalysis. Recently, the same group reported an enantioselective intramolecular aza-Michael addition of indoles using a similar binary catalyst system (Scheme 5.90) [91]. 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

Scheme 3.68. Cyclization/ring expansion for the construction of bridged polycyclic systems.

A novel approach towards the construction of the morphine skeleton is demonstrated by the total synthesis of ( )-desoxycodeine-D. One of the key steps for this synthesis is the palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic strategy for the construction of the polycyclic ring systems has provided an efficient access to the complete pentacyclic skeleton of morphine <00TL915>. 

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