Ring systems natural products synthesis

Another natural product synthesis using a metathesis as the key step has been reported to generate the ABCD ring system 133 of manzamine A. A multistep... 

The Heck reaction of 1,3 -diene systems via 7r-allylpalladium is also useful. This cyclization, which forms very congested quaternary carbon centers involving the intramolecular insertion of di-, tri- and tetrasubstituted alkenes, is particularly useful for natural products synthesis. In the synthesis of morphine, bis-cyclization of the octahydroisoquninoline precursor 112 by the intramolecular Heck reaction proceeded using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the 7i-allylpalladium intermediate 113, which attacks the phenol intramolecularly to form the benzofuran ring 114. Based on this method, the elegant total syntheses of (—)- and (+)-dihydrocodeinone, and (—)- and (+)-morphine (115) have been achieved [50],... 

These 107i-systems are isoelectronic with the pentalene dianion and have been of some theoretical interest. 1,5-Diheteropentalene systems are very popular substrates for the investigation of inter- and intramolecular cycloaddition reactions due to their diene character. Such cycloaddition processes allow for a rapid entry into complex polyheterocyclic rings and makes these compounds potentially useful for natural product synthesis. 

The potential utility of the 4//-furo[3,4-6]indole ring system in natural product synthesis was explored in an ellipticine (142) synthesis with an unexpected result <83TL5435, 84JOC4518, 91SL289). The reaction of compound (137) with 3,4-pyridyne (138) led to a mixture of the two possible cycloadducts, (139) and (140), in approximately equal amounts (Scheme 5), which were transformed into a readily separable mixture of isoellipticine (141) and ellipticine (142). 

Because of the excellent performance of the new catalysts, many research groups use ringclosing metathesis as the key step in natural product synthesis [12]-[18]. Scheme 6 shows some examples. Via ring-closing metathesis of the olefin 37 to the hydroazulene 38, Blechert et al. [12] succeeded in synthesizing a cyclic system which is part of many sesquiterpenes. Cyclooctane derivatives, whose synthesis is the main problem in taxol synthesis, can be obtained in good yields (39 40), as demonstrated by Grubbs et al. [ 13]. 

The intramolecular Heck reaction has been well established as a powerful tool for the construction of complex polycyclic ring systems in the context of natural product synthesis. 

The nickel-mediated [4 -i- 4] cycloaddition strategy has also provided a concise and stereocontroUed route into the sequiterpene lactone (+)-asteiiscanolide (128). The basic features of this approach are outlined in Scheme 17. The critical [4 + 4] cycloaddition st occurred under standard conditions to give the key intermediate in 67% yield. Clearly, the intramolecular version of the nickel-catalyzed diene cy-clodimerization has been established as a powerful and highly-selective protocol for the synthesis of cyclooctane ring systems and should find extensive qjplication to natural product synthesis. 

Corey and coworkers [45] later described the application of this reaction in the total synthesis of okaramine N (Scheme 9.16). Bisindole 110 was oxidatively cyclized using stoichiometric Pd(OAc)2 to form compound 111 in 38% yield. Although the yield was modest, the dihydroindoloazocine product could be elaborated in just two steps to afford okaramine N. This remarkably rapid synthesis highlights the efficacy of the palladium(II)-mediated oxidative Heck reaction to construct complex ring systems that can immediately expedite natural product synthesis. 

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