Construction of complex, polycyclic

Although the conversion of 63—>67 adequately expresses the utility of palladium-catalyzed cycloisomerizations for the construction of complex polycycles, the single-step, palladium-mediated conversion of compound 68 to the novel polyspirocycle 6930,31 (Scheme 15) can perhaps be regarded as the paragon of this chemistry. In this striking transformation, chemo- and regioselective... 

Since then, the photocycloaddition reaction has been extensively studied and has become a powerful tool for the construction of complex polycyclic molecules. High stereoselectivities are observed in some cases. The configuration of the diradical intermediate determines the stereochemistry of the adduct [33], Typical examples... 

In this section, those reactions in which the ylide is attached by a tether to the dipolaraphile resulting in an intramolecular cycloaddition will be discussed. To date, such a strategy has proved to be one of the less investigated aspects of azomethine ylide chemistry. However, intramolecular azomethine ylide technology, when combined with the excellent stereocontrol offered by cycloaddition reactions, allows for the rapid construction of complex polycyclic systems from relatively simple precursors. Consequently, it represents a highly attractive synthetic protocol that makes it a candidate for further investigation in the coming years. 

Substituted 7-pyrones are versatile synthetic precursors. There is strong precedent for the metalation4 and bromination5 of the 7-position, which allows 7-pyrones to be used in alkylation and aldol reactions and makes them attractive intermediates in the synthesis of polyacetate and spiroketal containing natural products.6 They can also be used as cycloaddition substrates in the construction of complex polycyclic systems as West has demonstrated.7 Furthermore, 7-pyrones have been used by Wender in an oxidopyrilium-alkene cycloaddition, a key reaction in his synthesis of phorbol.8... 

The cyclic ylide intermediate 366, as a 1,3-dipole, is generated by intramolecular reaction of Rh-carbene with the ketone in 365, and undergoes cycloaddition with n-bonds to give the adduct 367 [121]. When a-diazocarbonyls have additional unsaturation, domino cyclizations occur to produce polycyclic compounds. The Rh-carbene method offers a powerful tool for the construction of complex polycyclic molecules in short steps, and has been applied to elegant syntheses of a number of complex natural products. 

This strategy allowed for the rapid construction of complex, polycyclic skeletons in good yields from simple starting materials. 

The intramolecular Heck reaction has been well established as a powerful tool for the construction of complex polycyclic ring systems in the context of natural product synthesis. 

Regiochemical and stereochemical control can be excellent in many examples of the intermolecular photochemical [2 + 2] cycloaddition, but the frequency of cases where selectivity is low, or worse, unpredictable, has inhibited the use of this powerful reaction. While the major disadvantage of the inter-molecular photocycloaddition is its low selectivity in some systems, this problem can be substantially overcome by incorporating the two sites of unsaturation into the same molecule. Although many of the early examples of the [2 + 2] photocycloaddition were ntramolecular, this variation of the reaction saw only limited use until the 1970s when its potential for the rapid construction of complex polycyclic carbon skeleta was recognized by Oppolzer, Pattenden and others. 

Several detailed investigations of transannular IMDA cycloadditions have appeared in recent years. This transformation promises to become an important synthetic method owing to the potential for the rapid efficient construction of complex polycyclic ring systems. Other potenti strategic benefits include increased reactivity due to diminished entropic requirements (AS ). This is nicely illustrated by the facile cyclization of (101) with a tetrasubstituted dienophile, compared with the unsuccessful IMDA reaction of (102) (Figure 27). Although the cyclization of (101) proceeds with only moderate diastereoselection, many other examples have been reported that exhibit outstanding selectivity, e.g. cyclization of (103). It is conceivable that conformational constraints imposed by the macrocyclic system may lead to improved IMDA stereoselectivity relative to conventional acyclic trienes, but this point has not yet been demonstrated in any published examples. 

Tandem pericyclic reactions are a powerful strategy for construction of complex, polycyclic compounds. In recent years tandem [4 + 2]/[3 + 2] chemistry of nitro-alkenes and nitronates has been developed by Denmark et al. as a general approach to functionalized pyrrolidine-containing structures [118]. Within the subclass of inter [4 -I- 2]/intra [3 + 2] cycloadditions, they have documented the fused mode (/3-tether, Eq. 77), spiro mode (a-tether, Eq. 78), and bridged mode (a-tether, Eq. 79 or /3-tether, Eq. 80) constructions. These are highly stereoselective processes in the presence of Lewis acid such as SnCU and are amenable to asymmetric modification by use of chiral vinyl ethers. Finally, the nitroso acetals are readily transformed, by hydroge-nolysis, into polycyclic, a-hydroxypyrrolidinones, 4-aminocyclohexanones, and cyclo-pentylamines. 

Transition metal catalyzed intermolecular carbocyclization has been used in the construction of six-membered ring systems (10, 352) and provides a powerful approach to the construction of complex polycyclic systems. The rhodium-catalyzed intermolecular [2 - - 2 - - 2] carbocychzation of heteroatom-tethered 1,6-enynes with symmetrical and unsymmetrical alkynes affords the corresponding bicyclohexadienes in a highly efficient and regioselective... 

Domino sequences especially induced by the Pummerer reaction are well known to be very useful for the construction of complex polycyclic... 

The cascade rearrangements following double addition of alkenyl anions to the squarate ester was initiated by Paquette from the clue of Asensio s finding that twofold addition of organolithium (MeLi, PhLi, etc.) leads to the facile electrocyclic ring opening to 1,4-diketones [102]. This expedient method for construction of complex polycycles is achieved by a simple one-pot process... 

Acid-catalyzed cascade reactions are employed by nature and also by synthetic chemists in the construction of complex polycyclic molecules, including steroids (Section 4-7). Provide a mechanism for the following multiple cyclization. 

Vollhardt s total synthesis of strychnine successfully demonstrated the power of the cobalt-mediated [2+2+2]cycloaddition (111) for the construction of complex polycyclic molecules (Scheme 11). This key reaction was originally developed by his group in the 1970s, and widely utilized for the syntheses of complex natural and unnatural products (112-116). Here, this reaction was used for the simultaneous closure of the E and G rings with formation of the C7 quaternary center (117-119). To accomplish total synthesis, five synthetic approaches were investigated, but only the successful one is shown here. 

The Strychnos alkaloids possess diverse chemical structures that have attracted considerable attention in organic synthesis during the last decades. Recent studies on the synthesis of akuammicine, strychnine and leuconicine A and by Andrade et al. proved that the intramolecular Heck reaction is extremely valuable for the construction of complex polycyclic molecules. Based on Rawal s method for the construction of the D ring of Strychnos alkaloids, vinyl iodides 37, 39, and 42 undergo a regioselective and stereoselective palladium-catalyzed cychzation in the presence of Pd(OAc)2, PPha in Et3N to furnish ( )-akuammi-cine 38, and the advanced intermediates 40 and 43 in excellent chemical yields (Scheme 13.11). 

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