Construction of complex, polycyclic molecule

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... 

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. 

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). 

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. 

Diels-Alder reactions of conjugated cycloalkenones provide a very important method for rapidly constructing complex polycyclic molecules. Since cycloalkenones are very poorly reactive dienophiles, acceleration by special physical and catalytic methods is required in order to avoid high reaction temperatures and long reaction times which often lead to low product yields [8],... 

Orf/io-quinodimethanes have been used in numerous S3mthetic applications for the construction of various polycyclic ring systems found in structurally complex target molecules, via [4+2] Diels-Alder type cycloadditions. In this context, indolo-2,3-quinodimethanes have become increasingly useful as synthetic precursors to a variety of interesting [6]annelated indoles, carbazoles, and alkaloids [111]. 

The radical chemistry of organotins is overwhelmed by the tin hydride chemistry. In the past decades, the knowledge of kinetic parameters authorized the expeditious construction of complex molecules by using cascade radical reaction based on BujSn" methodology. Moreover, these strategies also offered an excellent dia-stereocontrol, especially for the construction of polycyclic skeletons. These synthetic applications of BujSnH, which will not be covered in this chapter, were reviewed in recent years [279]. In addition to the tin hydride chemistry, there are several applications of organotins in radical syntheses involving mainly allylstan-... 

The classical (Grignard-like) mechanism for Barbier reactions involves the primary formation of an Sm-alkyl species via halogen abstraction and subsequent reduction of the alkyl radical formed after the first electron transfer. Be that as it may, the Barbier reaction can be used to construct complex polycyclic target molecules, e.g. the synthesis of tetraquinanes from diquinane precursors by two independent intramolecular cyclization steps (Scheme 24) [83]. 

While rearrangement of propargylic esters to allenyl esters is facile, denouement of such intermediates is highly dependent on the presence of other multiple CC bonds in juxtaposi-tion. In any event, the generation of polycyclic compounds in one synthetic operation deserves serious consideration of the method for exploitation in the construction of significant and complex target molecules. 

Another approach is the use of multicomponent reactions (MCRs) to rapidly and efficiently construct structurally complex and varied polycyclic natural product-like compounds (Figure 1.5). A number of synthetic transformations played a key role in the rapid assembly of such molecules including isocyanide-based reactions, aza- and non-aza [4+2] cycloadditions, [3+2] cycloadditions, and dansition-metal-catalyzed reactions. Using isocyanide-based MCRs, pyrrolopyridines exemplified by mappicine represent an atttactive library target for their biological activity. Furthermore, the furoquinoline alkaloid tecleabine represents a common quinoline alkaloid core similar to strnctnres fonnd in a polycyclic library. ... 

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