Synthetic studies on the ingenane diterpenes. Construction of a tetracyclic 8-isoingenane model

Approaches to the synthesis of ingenol

“…The published approaches for the synthesis of ingenol include: (1) both inter-and intra-molecular [6 + 4] cycloadditions of tropones to dienes, [12][13][14] (2) intramolecular [4 + 3] cycloaddition of cyclic oxyallyls to a tethered furan, 15 (3) Lewis acid catalysed aldol cyclization, 16 (4) photo induced ring expansion-ring contraction, 17 (5) a ring contraction strategy based on the Ireland-Claisen rearrangement, 11,18 (6) transformation of an out-out system to an in-out isomer by [1,5]-hydrogen sigmatropy 19 and (7) intramolecular dioxenone photocycloaddition and fragmentation. 20 Only the latter three strategies provide the requisite inside-outside intrabridgehead stereochemical relationship of ingenol.…”

“…These thermally allowed cycloadditions produce a functionally rich BC ring building block for the construction of C-8-isoingenol intermediates. In his intermole- cular cycloaddition approach, 13 bridgehead enolate alkylation followed by aldol condensation was used to install the A ring of isoingenol (32 to 34). Regioselective dihydroxylation of the C ring followed by activation and treatment with sodiomalonate afforded a tetracyclic isoingenane 35 as shown in Scheme 4.…”

Studies on Intramolecular Higher-Order Cycloaddition Reactions

“…Tropone (2,4,6-cycloheptatrienone) ( 1 ) and its derivatives, on the other hand, have been found to be among the more effective 6π participants in higher-order cycloadditions . The bicyclo[4.4.1]undecane ring system that emerges from the thermally allowed [6 + 4] cycloaddition between tropone and various simple dienes is a principal substructural feature of several classes of natural products, including the tumor-promoting ingenane diterpenes, the unusual cerorubenate sesterterpenes, and the marine natural product, spiniferin-1 (Scheme ).

2

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Catalytic [6π+2π]-cycloaddition of Si-containing alkynes to 7-substituted 1,3,5-cycloheptatrienes under the action of Ti(acac)2Cl2–Et2AlCl

“…Among the available publications on this subject, of particular note is a series of works on the photochemical codimerization of CHT with alkenes, alkynes, and dienes in the presence of chromium complexes [2] and cycloaddition catalyzed by titanium [3] cobalt [4], and rhodium compounds [5]. In addition, polycyclic adducts based on CHT are valuable precursors in the synthesis of a number of compounds having high biological activities [6].…”

“…Among the available publications on this subject, of particular note is a series of works on the photochemical codimerization of CHT with alkenes, alkynes, and dienes in the presence of chromium complexes [2] and cycloaddition catalyzed by titanium [3] cobalt [4], and rhodium compounds [5]. In addition, polycyclic adducts based on CHT are valuable precursors in the synthesis of a number of compounds having high biological activities [6].Previously, we have developed the efficient methods for the selective cycloaddition of 1,2-dienes and acetylenes [7], 7-spirocyclopropylnorborna-2,5-dienes [8], a,u-diallenes, and a,udiacetylenes [9] to CHT in the presence of catalytic systems based on titanium complexes.As the development of these studies and in order to extend the scope of applicability of our method for the synthesis of polycyclic compounds of unique structure, we performed for the first time the [6pþ2p]-cycloaddition of Si-containing alkynes to 7-substituted CHT catalyzed by Ti(acac) 2 Cl 2 eEt 2 AlCl.The reaction of 7-alkyl(phenyl,allyl)-1,3,5-cycloheptatrienes with alkynes 1a-j taken in 1:1 M ratio catalyzed by the Ti(acac) 2 Cl 2 eEt 2 AlCl system carried out in benzene for 8 h at 80 С affords bicyclo[4.2.1]nona-2,4,7-trienes 2a-j in 79e88% yields, which were isolated by column chromatography (elution with petroleum ether) (Scheme 1) [15]. The addition of alkyne to the cycloheptatriene system occurs in the stereoselective manner to give mainly the syn-isomer.…”