Synthetic studies on the icetexones: enantioselective formal syntheses of icetexone and epi-icetexone

Abstract

Two strategies for the synthesis of the icetexane diterpenoids icetexone and epi-icetexone that rely on Ga(III)-catalyzed cycloisomerization of alkynyl indene substrates to yield fused [6-7-6] tricycles have been explored. In the first approach, access to a tricycle bearing a gem-dimethyl group paved the way for explorations of C–H functionalization of one of the methyl groups in close proximity to a hydroxyl-directing group. This approach was ultimately unsuccessful and led only to ring cleaved products. In the second approach, an alkynyl indene substrate bearing a cyano substituent was utilized, which was effective in providing a functional handle to access the icetexone subclass of diterpenoids. A key epoxide opening/diazene rearrangement sequence was utilized to complete a formal synthesis of icetexone and epi-icetexone, which is discussed in detail. Furthermore, the cyano-containing substrate has been prepared in enantioenriched form using a Rh-catalyzed conjugate addition reaction, which now provides a route to the enantioselective synthesis of these natural products.

Diterpenoids of terrestrial origin

“…111 Some synthetic studies in this area have been reported. 112 The taiwania quinones possess a 6 : 5 : 6 ring system in which the ve-membered ring B carries an aldehyde group. A number of syntheses of these diterpenes, including the ring contraction of sugiol methyl ether, have been reported.…”

Structure, Absolute Configuration, and Antiproliferative Activity of Abietane and Icetexane Diterpenoids from Salvia ballotiflora

“…Previous work on several populations of Salvia ballotiflora indicated that this species produced an interesting array of icetexane and abietane diterpenoids. Several members of this type of diterpenoids have been targeted for synthetic work due to their structural features and the biological activity exhibited by some icetexanes [ 16 , 17 , 18 , 19 , 20 ] as anti-proliferative activity, in vitro, against some human cancer cell lines [ 9 , 11 , 21 ]. On this issue, while the aqueous-methanolic extract of S. ballotiflora displayed cytotoxicity to Vero cells [ 22 ], the icetexane derivatives isolated from the chloroform extract of the same species showed cytotoxic activity, with 19-deoxyicetexone [ 23 ] being the most active compound against the HeLa cervical cancer cell line [ 21 ].…”

Structure, Absolute Configuration, and Antiproliferative Activity of Abietane and Icetexane Diterpenoids from <em>Salvia ballotiflora</em>

“…Crystals of anastasomosine (6) the calculation of the Flack [42] (x) and Hooft (y) parameters [43,44]. In the case of 6, these parameters were x = 0.1(2) and y = 0.09 (5), which for the inverted structure were x = 0.9(2) and y = 0.91 (5); while for 7 they were x = 0.07 (18) and y = 0.13 (9), which again for the inverted structure were x = 0.90 (17) and y = 0.87 (9). Crystallographic data (excluding structure factors) were deposited at the Cambridge Crystallographic Data Centre (CCDC) under the reference numbers CCDC 1570292 and CCDC 1570293, for 6 and 7, respectively, and copies of the data can be obtained free of charge on application to the CCDC, 12 Union Road, Cambridge CB2 IEZ, UK.…”

“…In turn, the thermochemical parameters associated with the VCD calculations of those conformers contributing to the final calculations are summarized in Table 4. parameters which were x = 0.07 (18) and y = 0.13 (9), and for the inverted structure were x = 0.90 (17) and y = 0.87 (9). In turn, a PLUTO plot of the molecular structure is shown in Figure 8.…”