Ophiobolins synthesis

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... 

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). 

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. 

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]. 

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. 

A tandem Brook and Claisen rearrangement of cyclopentenyl derivative 29 has been applied to the synthesis of naturally occurring sesquiterpene (a- )-ophiobolin C. The Ireland rearrangement of 29 results in substantial formation of C-silylated product543. 

Dauben and Hart have employed the ring contraction-ring expansion annelation sequence depicted in Scheme 34 to effect the first synthesis of the tri-cyclo[9,3,0,0 ]tetradecane ring system characteristic of the ophiobolin sester-terpenes. ... 

Two more papers on the synthesis of cyclic allenes have appeared which utilize the alkyl-lithium-induced opening of a fused dihalo-genocy clopropane such as (1 1 6 ). Access to the ophiobolin... 

In their total synthesis of (-i-)-ophiobolin in 1989, Kishi et al. found that treatment of a cyclopentenyl ester under the typical Ireland conditions gave principally C-silylated ester [63]. Heating of a C-silyl ester (prepared by acylation using a C-silyl acyl chloride) at 230 °C resulted in a 1,3-Brook rearrangement followed by an Ireland-Claisen rearrangement to give the desired product as a 6 1 ratio of isomers at C2 of the pentenoic acid (Scheme 4.63). The major product could have arisen through either a chair transition state of the Z-sUyl ketene acetal or a boat transition state of the E-silyl ketene acetal. 

A similar protocol has been applied by Wicha and co-workers in efforts toward the synthesis of a cyclopenta[8]annulene ring precursor to ophiobolin metabolites. Using BF3 OEt2 as a Lewis acid catalyst, epoxide ring opening of 87 resulted in the suprafacial 1,2-methyl shift followed by two consecutive hydride migrations to form ketone 88 in moderate yield. 

A novel variant on this theme is contained in Coates synthesis of (13), which contains the ring skeleton of the sesterterpene ophiobolin. In this case reductive fission of the cyclobutane ring [(12) - (13)] was used instead of the more usual retro-Aldol cleavage. 

Cycloadditions of a-chloroketenes to fulvenes are well documented and the adducts have also been applied to the synthesis of other natural products, including ophiobolin, filifolone, and chrysanthemic acid (Scheme 7.4) [5]. Nevertheless, Hong and coworkers [6] reported a new mode of reaction between a-halo acyl halides and 6,6-dialkoxyfulvene 20. Under standard conditions of in situ generation of a-chloroketenes, nucleophilic acyl substitution of the acyl chloride by... 

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