Domino cyclization natural products synthesis

Triquinanes 137 serve as good examples of a challenging framework in natural product synthesis [53]. In 2012, a domino radical cyclization to give vinylogous carbonates and carbamates was developed by Gharpure and coworkers [54], which involves an unprecedented, highly stereoselective formation of heterocyclic rings (Scheme 5.28). 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

Completion of the total synthesis afforded only six further steps, including the installation of the second 2-aminopyrimidine ring via a second domino sequence. This process presumably involves a conjugate addition of guanidine (2-293) to the enone system of2-292, followed by a cyclizing condensation and subsequent aromatization. Under the basic conditions, the ethyl ester moiety is also cleaved and 2-294 is isolated in form of the free acid, in 89 % yield. Finally, decarboxylation and deprotection of the amino functionality yielded the desired natural product 2-295. 

Furthermore, as described by Mori and coworkers, the domino aldol/cyclization reaction of the 3-keto sulfoxide 2-422 with succindialdehyde (2-423) in the presence of piperidine at r.t. afforded the chromone 2-424 which, on heating to 140 °C, underwent a thermal syn-elimination of methanesulfenic acid to provide 2-426 in 22 % overall yield (Scheme 2.100) [227]. This approach was then used for the synthesis of the natural products coniochaetones A (2-425) and B (2-427) [228]. 

The key step in this synthesis is the palladium-catalyzed domino- 1.6-enyne cyclization. which creates the bicyclic skeleton of the natural product in a single diastereoselective step. 

ABSTRACT In the synthesis of relevant organic compounds such as natural products and analogues, the proportion of the number of steps coupled with the increase of complexity is now a universal paradigm to ascertain the quality and efficiency of a process. Alongwith providing accessibility to a multitude of diversified classes of natural products such as alkaloids, terpenoids, steroids and others, these criteria have been addressed by us via the application of domino processes. The acid-catalyzed intermolecular cyclization has been used as a viable synthetic tool for the stereospecific formation of different classes of polycyclic natural products. 

The enantioselective total synthesis of the manzamine alkaloid ircinal A was completed in the laboratory of S.F. Martin utilizing a novel strategy. A domino Stille/Diels-Alder reaction was used to assemble the ABC ring core of the natural product. The vinyl bromide intermediate reacted with vinyl tributylstannane in the presence of Pd to afford the 1,3-diene moiety, which cyclized via an intramolecular Diels-Alder reaction to give the ABC core. 

In 2007, Chen and Zhu [21] detailed the total synthesis of the natural product using an acid-mediated domino P-ehmination/cyclization reaction (Scheme 14.7). 

The first total synthesis of this natural product was achieved by Chiu and Lam [139]. Key step of the synthesis is a rhodium-catalyzed domino cychza-tion/cycloaddition reaction to form the tricyclic core of the diterpenoid from hnear a-diazoketone 337. Concerning the mechanism of the reaction, it is hkely that the rhodium catalyst, when reacted with 337 at 0 °C, formed a carbenoid species which immediately cyclized to 341 (Scheme 14.53). This 1,3-dipole then underwent an intramolecular cycloaddition with the aUcene to give a mixture of two cycloadducts in 81% yield with 339 as the major product (dr= 1 3.1 338 339). The minor diastereomer 338 was probably formed via a less stable boat conformation of the tether in contrast to the chair conformation shown in 341, leading to the desired product Decreasing the temperature from 0 to —15 °C did not increase the dr but lowered the yield. It is also remarkable that the reaction afforded no more than 0.5 mol% of the rhodium(II)octanoate dimer ([Rh2(Oct)4]). Further transformation of 339 finally furnished (—)-indicol (340) in an overall yield of 10% over 21 steps. 

Murphy has investigated domino radical cyclizations of iodoaryl azides. This reaction found several applications in the total synthesis of natural product, as for instance Murphy s synthesis of aspidospermidine (Scheme 8.34), ° vindoline, horsfiline, and coerulescine. ... 

Usually, carbodiimides obtained by an aza-Wittig reaction of A-vinyUc phosphazenes with isocyanates cannot be isolated. Therefore, the very reactive carbodiimides can be used as synthetic intermediates of polyheterocyclic natural products by domino processes involving aza-Wittig/intramolecuIar cycUzation (AW-IC). In the synthesis of variolin B (58), the formation of the annulated 2-aminopyrimidine ring 57 is achieved from phosphazene 56 by a tandem aza-Wittig/carbodiimide-mediated intramolecular cyclization process (Scheme 15.12). 

Conventional multistep synthesis of natural products reduces the overall yield of the target molecules. In contrast, biomimetic enantioselective domino reactions, promoted by small-molecule artificial enzymes, are more useful for the practical synthesis of natural products and related compounds. The stereoselective formation of polycyclic isoprenoids by the cyclase-induced cyclization of polypren-oids is one of the most remarkable steps in biosynthesis because this reaction results in the formation of several new quaternary and tertiary stereocenters and new rings in a single step. The use of biomimetic polycyclization with artificial cyclase is the most ideal chemical method for the synthesis of these polycyclic terpenoids. In this chapter, biosynthesis of polycyclic terpenoids, biomimetic stereoselective polyene cyclization induced by artificial cyclases, and total synthesis of bioactive natural products using stereoselective polyene cyclization as a key step will be discussed. 

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