Cascade reactions carbocycle synthesis

If the oxidation is performed in the presence of an external dienophile, the respective products of [4+2] cycloaddition are formed [351-356]. Typical examples are illustrated by a one-pot synthesis of several silyl bicyclic alkenes 283 by intermolecular Diels-Alder reactions of 4-trimethylsilyl substituted masked o-benzoquinones 282 generated by oxidation of the corresponding 2-methoxyphenols 281 [351] and by the hypervalent iodine-mediated oxidative dearomatization/Diels-Alder cascade reaction of phenols 284 with allyl alcohol affording polycyclic acetals 285 (Scheme 3.118) [352]. This hypervalent iodine-promoted tandem phenolic oxidation/Diels-Alder reaction has been utilized in the stereoselective synthesis of the bacchopetiolone carbocyclic core [353]. 

Two-component cascade reactions are of paramount importance in the synthesis of cyclic products. There are a lot of examples in organocatalysis dealing with different reactants and activation modes. We wiU try to summarize the most relevant ones. First, we will describe the synthesis of different carbocycles based on the ring size. Then we will focus on cascade reactions that render acyclic compounds. 

The synthesis of carbocycles via a two-component cascade reaction in an asymmetric fashion has attracted much attention from the chemical community. Due to his importance in natural products, the synthesis of cyclopropanes, cyclopentanes, and cyclohexanes has been one of the common goals for organocatalytic methodologies. The high stereoselectivity achieved, green procedures, and soft conditions make this organocatalytic approximation one of the most attractive ones to build complex cyclic scaffolds. 

Palladium and chiral amine co-catalyzed enantioselective dynamic cascade reaction of simple starting materials leads to the synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter (Scheme 6.14) [16]. 

Ma, G., Afewerki, S., Deiana, L., Palo-Nieto, C., Liu, L., Sun, J., Ibrahem, I., Cordova, A. (2013). A palladium/chiral amine co-catalyzed enantioselective dynamic cascade reaction synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter. Ange-wandte Chemie International Edition, 52, 6050-6054. 

Miscellaneous Gold- and Iron-Catalyzed Cascade Reactions The car-benic reactivity of gold catalysis was exploited toward the synthesis of stereoselective six-membered ring carbocycles, through cyclopropanation reactions incorporated in cascade sequences [31]. 

In 2001, Larock and Tian reported a palladium-catalyzed cascade reaction of aryl halides and 1-aryl-l-aIkynes to synthesize 9-aIkylidene-9/f-fluorenes 167 [66] (Scheme 6.44). Based on the active role of Pd(IV) in organopalladium chemistry, the authors proposed a mechanism involving the formation, transformation, and reductive elimination of Pd(IV) intermediates and aryl C—H bond activation. It is noteworthy that both carbocyclic and heterocyclic aryl iodides, such as pyridine and thiophene, could be introduced in this reaction. Later, Zhao and Larock reported an efficient palladium-catalyzed cascade reaction for the synthesis of substituted carbazoles 169 from A/-(3-iodophenyl)anilines 168 and alkynes [67] (Scheme 6.45). 

Inspired by the success of intramolecular addition and tautomerization of aldehydes with a pendant alkyne through cooperative catalysis of a secondary amine and an An complex, in 2008, Yang et al. reported a cascade reaction with the combination of a copper complex and an achiral secondary amine catalyst for the synthesis of attractive carbocycles [48]. This chemistry merged a pyrrolidine-promoted Michael addition via iminium ion intermediates and a Cu-catalyzed cycloisomerization protocol (Scheme 9.54). Various ketones and alkyne-tethered active methylene compounds could be converted into densely functionalized cyclopentene derivatives. Although the asymmetric version was not given, the chemistry described here was amenable for the implementation of asymmetric synthesis of such functionalized molecules by a combination of chiral amines and suitable Au complexes. 

The identification of novel ways to incorporate an asymmetric intramolecular Mizoroki-Heck reaction as part of a cascade cyclization sequence has led to attractive approaches for assembling complex polycyclic molecules. Keay and coworkers [54] reported the use of a double Mizoroki-Heck cyclization as the pivotal step in the asymmetric total synthesis of xestoquinone (93), a reduced congener of halenaquinone (Scheme 16.20). In this step, naphthyl triflate 90 was cyclized with Pd2(dba)3 (dba = dibenzylideneace-tone), (5 )-BINAP and 1,2,2,6,6-pentamethylpiperidine (PMP) in toluene at 110°C to give pentacyclic product 92 with impressive efficiency and moderate enantioselectivity. This conversion proceeds by initial asymmetric 6-exo Mizoroki-Heck cyclization to form the central six-membered carbocycle and install the benzylic quaternary stereocentre. The first cyclization event is followed by a second Mizoroki-Heck reaction in which neopentyl... 

Xue H, Yang J, Gopal P. Toward the synthesis of norzoanth-amine building carbocyclic core by a transannular Michael reaction cascade. Org. Lett. 2011 13 5696-5699. 

A new gold-catalysed 6 Cf-endo-dig carbocyclization of dialkynylbenzenes (256) has been developed as a method for the synthesis of 1,3-disubstituted naphthalenes (257) (NuH = ROH, RR NH, Ar-H). For substrates with R = 2-PhC=C-C6H4 the reactions continues as a cascade, providing disubstituted chrysenes. ... 

---