Synthesis cyanthiwigin

Cyanthiwigin synthesis 180 Cyclobutane synthesis 76, 102 Cycloheptane synthesis 53,165, 169, 180,... 

The cyanthin diterpenes show physiological activity ranging from cytotoxicity to nerve-growth factor stimulation. Andrew J. Phillips of the University of Colorado recently described (J. Am. Client. Soc. 2005,127,5334) a concise cnantioselective synthesis of cyanthiwigin U 3, based on the metathesis conversion of 1 to 2, using the second generation Grubbs catalyst. 

In summary, the Phillips group accomplished the enantioselective total synthesis of (+)-cyanthiwigin U (1) in twelve linear steps with an overall yield of nearly 11%. The synthesis is characterized by a minimal use of protecting groups and an impressive domino metathesis sequence. 

The DAAA has successfully been applied as a key step in the total synthesis of a number of natural products due to its ability to generate quaternary carbon centres enantioselectively. For example (-H)-dichroanone (81), [42] oxybutynin, [43] (-)-cyanthiwigin F (84) [44] and other examples (Scheme 4.22) [45, 46]. As alluded to above the DAAA has also been extended to the asymmetric synthesis of a-fluorinated cyclohexanones, an important class of compounds for medicinal chemistry [47]. 

Similarly, the bicyclo[2.2.2]octene double bond in 28 was readily opened in a domino ROM/double RCM process, leading to tricyclic bisenone 29 with catalyst 2 under ethylene atmosphere in good overall yield from dialdehyde 27 (Scheme 2.11) [7]. Compound 29 was successfully utihzed as the key intermediate in a total synthesis of the bioactive diterpenoid (-l-)-cyanthiwigin U. 

Scheme 14.45 Total synthesis of (-l-)-cyanthiwigin U (295) by Phillips and coworkers (DMP, Dess-Martin periodinane).

The first total synthesis of (-l-)-cyanthiwigin U was accomplished in 12 steps and 17% overall yield by the group of Phillips in 2005 (Scheme 13.23) [28]. Key of the synthesis featured an efficient two-directional tandem metathesis which converted the... 

Total Synthesis of (-)-Cyanthiwigin F by Decarboxylative Asymmetric Allylation... 

Stoltz et al. reported enantioselective synthesis of (—)-cyanthiwigin F via double decarboxylative asymmetric allylation of bis(allyl P-ketocarboxylates) (Scheme 8.10) [34]. Initially, two molecules of diallyl succinate (57) was condensed under basic conditions to give a cyclic bis(P-ketoester), which was then methylated to afford an isomeric mixture of 58. Subsequent treatment with a chiral palladium catalyst induced double decarboxylation of those allyl P-ketoester moieties to afford a chiral cyclohexan-l,4-dione 59 (99% ee) along with its meso isomer. The enantiomeric excess of the product was enhanced through the double asymmetric allylation reaction. The cyclo-hexanedione 59 was converted into (-)-cyanthiwigin F through further six steps. 

In order to test this principle, Enquist and Stoltz submitted compound 107, which consisted of a 1 1 mixture of the racemate and the weso-compound to the standard decarboxylative allylic alkylation protocol. The reaction resulted in a mixture of chiral diketone 108 and the wteso-diastereomer 109 in a ratio of 81 19, the total yield amounting to 78%. More remarkably, the enantiomeric excess of the major product R,R)-108 was found to be 99% ee. The result indicates that, after the two stereogenic centers of the starting material have been subsequently bulldozed, the chiral catalyst exerts stereocontrol in the allylation of the enolate. The main diastereomer 108 was separated and served as a key intermediate in a total synthesis of the marine diterpenoid cyanthiwigin F along with the lower homolog (R = H) (Scheme 5.34) [57]. 

In 2008, Stoltz and Enquist disclosed a novel approach to the total synthesis of the related cyathin diterpenoid (—)-cyanthiwigin F (119) [80]. They applied a simultaneous alkene RCM and cross metathesis (CM) protocol to achieve the required closure of the seven-membered ring as well as elaboration of the terminal allyl group (Fig. 31). This process was effectively and selectively conducted by treating polyene (120) with Grubbs-Hoveyda catalyst (81) and a vinyl boronate species to produce the desired bicycle (121) in 51% yield. 

SCHEME 7.29. Synthesis of cyanthiwigin F using double catalytic enantioselective aUylation. 

SCHEME 13.44. Asymmetric enolate alkylation in the synthesis of cyanthiwigin F. 

PhiUips et al. designed the tandem RRM reaction of bicyclic compounds having two reactive sites in side chains to synthesize a tricyclic diterpenoid cyanthiwigin U 137, which is isolated from both fungal and marine sources (Scheme 24.35). The two-directional tandem ROM-RCM sequence of bicyclo[2.2.2]-octane 135 was catalyzed by [Ru]-II (20mol%) under the ethylene atmosphere, and transformations of tricyclic compound 136 completed a synthesis of this natural product in 17% overall yield in 12 steps. 

The usefulness of this reaction was highlighted in the total synthesis of marine diterpenoid (—)-cyanthiwigin, which was isolated from the sea sponge Myrmekioderma Styx and shown to exhibit cytotoxic activity against human primary tumor cells (with a half-maximal inhibitory... 

Trisubstituted olefins embedded in seven-membered carbocycles are also synthesized in high yields from the corresponding 1,8-dienes. In their elegant total synthesis of (—)-cyanthiwigin F (276), Stoltz and Enquist used for the first time catalyst (Ru]-X [49] possessing an increased activity for the generation of trisubstituted olefins. A double Pd-catalyzed decarboxylative allyUc alkylation of 277 in... 

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