Tetracyclic scaffold

Another effective combination of two radical cyclization steps has been demonstrated by Sha and coworkers during the course of the first total synthesis of (+)-paniculatine (3-24), a natural alkaloid belonging to the subclass of Lycopodium alkaloids [13]. 3-24 has a unique tetracyclic scaffold with seven stereogenic centers [14]. Although no special features of (+)-paniculatine have so far been documented, other Lycopodium alkaloids are reported to be potent acetylcholinesterase inhibitors, or show promising results in the treatment of Alzheimer s disease [15]. When... 

The biomimetic cationic domino cyclization of an acyclic unsaturated substrate to give the tetracyclic scaffold of triterpenes and steroids is intensively described in the literature.1121 The concept has recently been used by Corey et al. to prepare enanti-opure (+)-dammarenediol II 18 in an exceptional short way.1131 The synthesis demonstrates the power of the combination of cation-olefin polyannulation with the aldol cyclization for tetraannulation (scheme 4). Successive treatment of the acylsilane 13 with 2-propenyllithium 14 and the iodoalkane 15 efficiently yidds the epoxytriene 16. The Lewis acid... 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

The first main tetracyclic intermediate with an ergoUne 2 scaffold in the biosynthesis of fumigaclavines was detected as 8 in A. fumigatus, whereas another intermediate with tetracyclic scaffold was determined as 15 in P. commune. Both structures contain a saturated D-ring, which are different in their stereochemistiy at C-8. In comparison, 8 and downstream enzymatic products of A. fumigatus. 

Finally, the most recent efforts of the Hong group provided the tetracyclic scaffold of steroids in a two-component, three-step Michael/Michael/aldol/Henry cascade (Scheme 14.8c) [19]. The preferred catalyst ent)-ll, however, could not deliver the high diastereoselectivity that was obtained in the previous syntheses (56 44 dr). The excellent enantiomeric excess (98/99% ee), on the other hand, encouraged further development of the cascade (Scheme 14.8c). After the Michael/Michael sequence, the medium was acidified to complete the Robinson annulation to enone 64. Interestingly, subsequent treatment with only 0.5 equiv of tetrabutylammonium fluoride (TBAF) effected a very fast reaction to the target tetracycle (63%) at low temperature. 

Equally nitrogen-rich products were produced by Trost and coworkers in 2009 [44]. Their goal was to synthesize agelastatins that harbor an interesting stere-ogenic and highly functionalized tetracyclic scaffold. To this end, they employed a palladium-catalyzed dialkylation reaction between bisallylic carbonate 181 and 2-pyrrolamides 182 (Scheme 14.23). 

A recent extension of the DTS is the concept of collective total synthesis, which has been introduced by MacMillan in 2011 [94]. Collective total synthesis aims for the generation of structurally diverse natural products by transformation of a common synthetic scaffold through biomimetic-like pathways [95]. MacMillan et al. employed the common tetracyclic scaffold 120 for the complex total synthesis of six different opium alkaloids of considerable structural complexity (Scheme 15.25) [94]. 

Two groups have since taken advantage of this cascade-type approach for the synthesis of berkelic acid. Fananas et al. [161] modified their method to incorporate the final ring of the tetracyclic scaffold and adapted the sequence to the large-scale synthesis of 96 (Scheme 75). 

Based on this reaction, solid-phase library synthesis of tri- and tetracyclic scaffolds was developed by using Tenta-Gel resin (a poly(ethyleneglycol)-polystyrene copolymer) derivatized with a photolabUe linker as a solid support. Because of an epoxy functionality, the TiCLi-catalyzed trans-esterifcation used in the solution-phase reaction had to be replaced with a direct acylation by using a coupling reagent. Resin-bound epoxycyclohexenol 121 was reacted with the nitrone carboxylic acid 122 in the presence of PyBroP to form a nitrone cyclohexenyl ester intermediate that was... 

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