Enantioselective cycloaddition strategies

The main strategy for catalytic enantioselective cycloaddition reactions of carbonyl compounds is the use of a chiral Lewis acid catalyst. This approach is probably the most efficient and economic way to effect an enantioselective reaction, because it allows the direct formation of chiral compounds from achiral substrates under mild conditions and requires a sub-stoichiometric amount of chiral material. 

Helicenes and helicene-like molecules possessing nonplanar ortho-fused scaffolds exhibit helical chirality. Enantiopure forms of these molecules are potentially applicable to optical or electronic functional materials and chiral reagents [1], Therefore, development of their practical enantioselective synthesis, which can introduce various substituents on their frameworks, is highly attractive. The classical nonasymmetric synthesis of helicenes is based on an oxidative photocyclization of stilbene-type precursors [2]. However, this method suffers from low product yields and low substrate concentrations. Thus, several nonphotochemical synthetic methods have been developed which have been applied to the synthesis of enantioenriched helicenes [3]. Among them, a [2 - - 2 - - 2] cycloaddition strategy is highly attractive because of its convenient operation and its applicability to the catalytic enantioselective synthesis. The synthesis of helicenes and helicene-like molecules by transition-metal-mediated [2 -I- 2 -I- 2] cycloaddition reactions, including enantioselective variants, is summarized in this section. 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

Some of the strategies for the control of regio-, diastereo-, and enantioselectivity in 1,3-dipolar cycloaddition reactions are shown below. These methods have been realized to some degree in recent years, and will form the basis of the discussion in this chapter. 

In summary, the metal-catalyzed decomposition of diazo compounds results in a broad array of opportunities for the development of new asymmetric catalytic transformations. In the last few years considerable advances have been made in enantioselective intermolecular C-H insertion, novel cycloadditions, and tandem cyclization/cycloadditions. These new transformations offer new strategies for the rapid enantioselective construction of complex structures. 

Itoh T, Nagata K, Miyazaki M, Ishikawa H, Kurihara A, Ohsawa A (2004) A selective reductive amination of aldehydes by the use of Hantzsch dihydropy-ridines as reductant. Tetrahedron 60 6649-6655 Jen WS, Wiener JJM, MacMillan DWC (2000) New strategies for organic catalysis The first enantioselective organocatalytic 1,3-dipolar cycloaddition. J Am Chem Soc 122 9874-9875... 

Following the same strategy, further improvements in similar catalytic asymmetric [4 + 2] cycloaddition reaction have been made by Lectka group. The cyclic 1,4-benzoxazinones 3 (Scheme 10.4) that rely on the highly enantioselective [4 + 2] cycloaddition of o-benzoquinone imides with chiral ketene enolates were efficiently constructed, which can be derivatized in situ to provide a-amino acid derivatives in good to excellent yields and with virtual enantiopurity [9]. 

A similar strategy was followed by Konoike et for the enantioselective total synthesis of ( + )-6-epi-mevinolin and its analogues. Intramolecular cycloaddition of chiral (Z)-trienone 73 led to a mixture of r/.s-dccalins 74 and 75 (Scheme 7.17) the most satisfactory result was achieved when the reaction was... 

The vast majority of strategies aimed at effecting enantioselective Diels-Alder reactions rely on complexation of an unsaturated carbonyl compound to a chiral Lewis acid, but this is not the only catalytic method for achieving enantiofacial bias. A unique approach outlined in Scheme 52 takes advantage of a diene (or precursor) possessing an acidic proton [138] treatment with a catalytic amount of a chiral base results in transient formation of an oxidodiene which undergoes oxyanion-accelerated cycloaddition with a maleimide [139]. 

Strategy of Rh-triggered qrcloaddition cascade. In this case, the Rh-catalyzed transformation of a-diazoketone 132 into an oxatetracycUc key cycloadduct 133 through intramolecular [3+2]-cycloaddition of an in-situ generated carbonyl yUde was achieved. Further, the regioselective conversion of the cycloadduct 133 into a tropolone derivative led to an efficient enantioselective access to colchicine (Scheme 40). 

Catalytic enantioselective [4+2] cycloaddition A strategy to access aza-hexacycles 13CSR902. 

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