Cascade reactions natural product synthesis

As model studies and radical reactivity control have improved, the so-called cascade (or domino) reactions have emerged as a very powerful method for natural product synthesis, since they offer a unique route to prepare complex backbones from appropriately designed but quite simple precursors. A few selected reactions will be presented here. 

The cascade sequences presented herein demonstrate unprecedented modes of reactivity in Nazarov chemistry that are initiated by the silver(I)-promoted ring opening of halocyclopropanes. The ease with which the gem-dichlorocyclopropanes can be prepared, the relatively mild reaction conditions, and the efficiency of these processes make these substrates attractive intermediates for an application in natural product synthesis. 

The formation of /3-hydroxyselenides through the reaction of a selenium-stabilized carbanion with carbonyl compounds has been extensively used also in the context of natural product synthesis. The phenylselenoalkyllithium compound 115 was reacted with aldehyde 116 to afford /3-hydroxyselenide 117. In a radical cyclization cascade the tricyclic molecule 118 was generated in good yields and subsequent transformations led to the synthesis of pentalenene 119 (Scheme 28).1 9 Also other natural products like zizaene and khusimone have been synthesized via a similar route.200... 

Overman and Pennington have developed a versatile methodology for stereoselective tetrahydrofuran synthesis based on pinacol terminated Prins cyclizations. The general reaction is outlined in Scheme 63. A review on the strategic use of these cascade reactions in natural product synthesis has been published <2003JOC7143>. 

MacMillan et al. demonstrated the power of a Diels-Alder reaction for the construction of complex organic scaffolds toward efficient natural product synthesis. They recently developed a cascade reaction, including an asymmetric DA between indol derivatives 23 and propargyl aldehyde catalyzed by 24 or 25 as the key step (Scheme 6.5) [20]. Depending on X (S or Se), the cascades proceed through different paths to give the different polycychc natural product precursors 26 and 27. 

The first chapter provides an informative introduction to this area of biomimetic natural product synthesis, in particular focusing on the role of electrocyclisation reaction cascades, from K.C. Nicolaou s seminal synthesis of the endiandric acids, to the more recent research carried out on the tridachiahydropyrones and related sacoglossan metabolites. The thesis then sets out to explore the hypothesis that these secondary metabolites function as photo-protective membrane antioxidants, shielding the producing organisms from the damaging effects of UV radiation. 

Volhardt s tZZ-estrone synthesis was the first application of a transition-metal-catalyzed [2 -1- 2 -I- 2] alkyne cyclotrimerization in natural product synthesis, and the overall beauty of the synthetic sequence is still appealing [4,5]. Undoubtedly, this brilliant synthesis is a classic in its field. Following a D ABCD ring formation approach, the tetracyclic core of estrone was produced in a single reaction step by profiting from a reaction cascade that started with a cobalt-mediated crossed [2 + 2 + 2] alkyne cycloaddifion, which was followed by a benzocyclobutane to o-quinodimethane rearrangement, and was finalized by an intramolecular Diels-Alder reaction (Scheme 7.2). 

The purpose of this chapter is to describe the use of epoxides as biosynthetic precursors for cyclic ethers. The advances that allow for predictable chemical synthesis based on epoxide opening, including the development of models for regiocontrol in intramolecular ring-opening reactions and stereoselective synthesis, will be described. Numerons examples of epoxide cascade reactions in natural product synthesis will conclude the chapter. 

Although no natural product synthesis has yet to be completed by a cascade in water under neutral conditions, the Jamison group has used the protocol to prepare the impressively complex tetfa-tetfahydropyran core of the ladder toxin gymnocin (188 Scheme 4.43) [78]. Triepoxide 189 was heated to 80°C in water for 9 days to yield 188 in 35% yield. The reaction rate was slower than previously observed rates because the final cyclization step was sluggish. The authors... 

Org. Eiomol. Chem., 6, 2037-2045 For a review about natural product synthesis using cascade reaction strategies, see (d) Nicolaou, K.C., Edmonds, D.)., and Bulger, P.G. 

In the previous section we have shown that tandem ene-yne-ene RCM has been broadly used for the rapid and efficient construction of complex frameworks. In principle, selective alkene metathesis can be combined with other types of transformation to achieve a cascade reaction, which will provide a tremendous increase in molecular complexity [77]. Therefore, in this section, we highlight several recent examples of cascade reaction involving selective alkene metathesis for natural product synthesis. 

Phillips laboratory also extended the domino process in natural product synthesis by combining ROM, RCM, and CM. For this cascade reaction, regioselectivity... 

When cascade reaction involving metathesis is applied in the complex natural product synthesis, proper sequence of multistage metathesis processes is crucial. The following example underscores this point. In 2006, Hoye and coworkers reported the total synthesis of (+)-gigantecin (125) [82]. In this work (Fig. 33)... 

APPLICATION OF ORGANOCATALYTIC CASCADE REACTIONS IN NATURAL PRODUCT SYNTHESIS AND DRUG DISCOVERY... 

Amine-catalyzed cascade reactions in natural product synthesis... 

Iminium-Ion-Catalyzed Cascade Reactions in Natural Product Synthesis... 

The enamine (/dienamine)-iminium cycle-specific cascade catalysis is an important constituent of amine-catalyzed cascade reactions [10]. This strategy has been explored extensively and also applied to natural product synthesis. One such example is the total synthesis of dihydrocorynantheol, which was first isolated from the bark of Aspidosperma marcgravianum in 1967 [29]. This indole alkaloid is a member of the corynantheine and was found to exhibit antiparasitic, antiviral, or analgetic activities, which have attracted considerable attention from the synthetic community. Among those reported total syntheses, Itoh et al. developed a Mannich-Michael cascade reaction catalyzed by L-proline 52 for the total synthesis of ent-dihydrocorynantheol 54 (Scheme 3.8) [30], The cascade reaction of 3-ethyl-3-buten-2-one 51 with dihydro-P-carboline 50 catalyzed by 30mol% of (S)-proline afforded the tetracyclic core structure 53 in 85% yield. Excellent stereoselectivity was achieved in this cascade reaction (99% enantiomeric excess and almost complete diastereomeric control). Therefore, this organocascade reaction could lead expeditiously to construction of the core structure, which enabled the authors to accomplish the total synthesis of enl-dihydrocorynantheol 54 in just five steps. 

---