Ophiobolin

Numerous applications of the Ni(n)/Cr(ii)-mediated coupling reaction in total synthesis have already been reported.11 Some of the more noteworthy examples derive from Kishi s laboratories and played a role in the syntheses of such complex molecules as (+)-ophiobolin C16 and halichondrin B17 (see Scheme 5). Another elegant application can be found in the enantioselective total syntheses of (+)-brefeldin C and 4-ep/-brefeldin C by Schreiber and Meyers (see Scheme 5).18... 

Ojima-Holton method 670 olefin insertion 569 (+)-ophiobolin C 716 f. organoselenides 397 ortlio-quinodimethane 155 f.,... 

The [4+ 4]-cycloaddition reaction of tethered bis-dienes has been used by Wender and co-workers in total synthesis as exemplified in syntheses of ( )-salsolene oxide and (-l-)-asteriscanolide (Scheme 28). In the synthesis of ( )-salsolene oxide, a nickel(0)-catalyst cleanly effects the cycloaddition of the two conjugated dienes in compound 93 to afford the bicyclo[5.3.1]undecadiene in a good yield and with moderate selectivity.99 The first synthesis of (-l-)-asteriscanolide was accomplished in only 13 steps. The key [4+ 4]-cycloaddition reaction efficiently set the requisite eight-membered ring of (-l-)-asteriscanolide in good yield and with excellent diastereoselectivity.100 The diastereoselective [4 + 4]-cycloaddition has also been applied to the synthesis of the core ring system found in several sesterterpenes such as the ophiobolins (Scheme 28).101... 

The bicyclic ketone (555) was treated with cyclopentenyllithium (354) at —78 °C to form the intermediate (555), which underwent a rapid Cope rearrangement to the intermediate (356). By treatment of (356) with methyl iodide, compound (357) was obtained. The ketone (357) would serve as an intermediate in the synthesis of ophiobolin A (358) 124). 

AuTK, Chick WSH, Leung PC, The biology of ophiobolins. Life Sci 67 733—742,... 

A novel entry to decahydrocyclopentacyclooctene derivatives via the intramolecular photocycloaddition of fused a,/3-unsaturated y-lactones has been developed (80CC1011). Irradiation of the butenolide (153) in acetone solution gave both the fused and bridged photoadducts (154) and (155) (2-3 1). The major adduct was hydrolyzed, oxidized and esterified to afford (156). Reductive cleavage of the unsaturated keto ester (156) with lithium in ammonia afforded a five-component mixture of a,/3- and /3,y-unsaturated esters. Equilibration with 0.1M sodium methoxide in methanol converted the mixture into a single a,j8-unsaturated ester (157 Scheme 34). This annelative two-carbon ring expansion method may find application in the synthesis of ophiobolin and ceroplastol sesterterpenes. 

Ophiobolin A] Cochliobolus setariae, Bipolaris spp. CaM-PDE, CaM (reacts with lysine... 

We have recently isolated two new ophiobolins, G and H, from a novel source, Aspergillus ustus (ATCC No. 38849) (16) (Figures 5 and 6). Structurally, these two compounds are interesting in that the ring fusion between rings A and B is trans, as opposed to cis in the ophiobolins previously described from other fungal sources. In this respect these new metabolites more closely resemble the ophiobolins extracted from insects. Structural features common to both the insect and fungal ophiobolins are the double bonds at C7-C8 and C18-C19. Ophiobolins G and H are unique in the possession of a C16-C17 cis double bond. 

S-8-S carbon skeleton of Aisicoccins and ophiobolins (equation 10). Trisubstituted alkenes yield keto acids (equation 11). A related reaction, known as the Lemieux-von Rudloff (periodate-permanganate) oxidation, is also used to oxidize alkenes to acids or ketones (equation 12). If aldehydes are required... 

Similar strategies were used by Booker-Milburn et al. in approaches toward the synthesis of dictyol C and a-eudesmol [215], and by Blake et al. in approaches toward the synthesis of ophiobolin F and fusicoccin A [216]. 

Mehta has examined relative stereocontrol in an approach to the carbocyclic nucleus of ophiobolins. Cyclization of the triquinane (11) gave two products, (12) and (13), in a 4 1 ratio (Scheme 14). These products arise from opposite rotatory pathways as shown. Surprisingly, the major product arises from conrotation to the concave face of the diquinane unit. Finally, Nazarov has provided an interesting example of both fused and spiro mode annulations in equation (10). ... 

Another common strategy for construction of fused cyclooctanones is to first build a fused cyclobutanone by [2 + 2] cycloaddition of a vinylketene to a cycloalkene. Equation (58) illustrates this approach with Paquette s synthesis of the tricyclic skeleton of the ophiobolins. Cyclobutanone (108) is assembled by addition of a vinylketene to cyclopentadiene. Cyclopentenyllithium then adds to the less-hindered face of (108), and the lithium alkoxide undergoes a spontaneous anionic oxy-Cope rearrangement to afford the central cyclooctane ring. 

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